A second-generation eIF4A RNA helicase inhibitor exploits translational reprogramming as a vulnerability in triple-negative breast cancer

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new collection</label> </li> <li> <input type="radio" id="collections-action-panel-existing" class="collections-existing" name="collections" value="existing" checked="true" data-ga-category="save_share" data-ga-action="collections" data-ga-label="collections_radio_existing"> <label for="collections-action-panel-existing">Add to an existing collection</label> </li> </ul> </div> <div class="controls-wrapper"> <div class="action-panel-control-wrap new-collections-controls"> <label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk"> Name your collection: </label> <input type="text" name="add-to-new-collection" id="collections-action-panel-add-to-new" class="collections-action-add-to-new" pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/" maxlength="100" data-ga-category="save_share" data-ga-action="create_collection" data-ga-label="non_favorties_collection"> <div class="collections-new-name-too-long usa-input-error-message selection-validation-message"> Name must be less than 100 characters </div> </div> <div class="action-panel-control-wrap existing-collections-controls"> <label for="collections-action-panel-add-to-existing" class="action-panel-label"> Choose a collection: </label> <select id="collections-action-panel-add-to-existing" class="action-panel-selector collections-action-add-to-existing" data-ga-category="save_share" data-ga-action="select_collection" data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'"> </select> <div class="collections-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your collection due to an error<br> <a href="#">Please try again</a> </div> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore data-ga-category="save_share" data-ga-action="collections" data-ga-label="add"> Add </button> <button class="action-panel-cancel" aria-label="Close 'Add to Collections' panel" ref="linksrc=close_collections_panel" aria-controls="collections-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="collections" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="bibliography-action-panel" class="bibliography-action-panel action-panel in-progress-dots-panel" aria-hidden="true" data-bibliography-open-panel-enabled="false" data-bibliography-open-panel-url-hash="#open-bibliography-panel"> <div class="inner-wrap"> <h3 class="action-panel-heading"> Add to My Bibliography </h3> <form id="bibliography-action-panel-form" class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors" data-add-to-bibliography-max-amount="100" data-add-to-bibliography-batch-size="10" data-bibliography-delegates-url="/list-bibliography-delegates/" data-add-to-bibliography-url="/add-to-bibliography/" data-get-article-ids-by-search-url="/get-article-ids-by-search/" data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/"> <input type="hidden" name="csrfmiddlewaretoken" value="WY7RoPgz7GN0tOJ7Vx2v6awyJUGrCoIkKU3S9an6pJPU0a1p0RX0CMmeqNTP2fr6"> <div class="action-panel-control-wrap bibliographies-controls"> <div class="choice-group"> <ul class="bibliographies-action-add radio-group-items"> <li> <input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/> <label for="my-bibliography">My Bibliography</label> </li> </ul> </div> </div> <div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your delegates due to an error<br> <a href="#">Please try again</a> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore> Add </button> <button class="action-panel-cancel" aria-label="Close 'Add to bibliography' panel" ref="linksrc=close_bibliography_panel" aria-controls="bibliography-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="mybib" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true" data-saved-search-open-panel-enabled="false" data-saved-search-open-panel-url-hash="#open-saved-search-panel"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Your saved search </h2> <form id="saved-search-action-panel-form" class="saved-search-action-panel-form action-panel-content action-form" data-create-saved-search-url="/create-saved-search/" data-try-search-terms-url="/try-search-term/" data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/"> <input type="hidden" name="csrfmiddlewaretoken" value="WY7RoPgz7GN0tOJ7Vx2v6awyJUGrCoIkKU3S9an6pJPU0a1p0RX0CMmeqNTP2fr6"> <div class="action-panel-control-wrap"> <label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk"> Name of saved search: </label> <input maxlength="200" type="text" name="saved-search-name" id="saved-search-name" class="saved-search-name" value="" required pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"> </div> <div class="action-panel-control-wrap"> <label for="saved-search-term" class="action-panel-label required-field-asterisk"> Search terms: </label> <textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea> </div> <div class="test-search-term-wrap"> <a href="#" class="try-search-term">Test search terms</a> </div> <div class="choice-group action-panel-extra-margin-top"> <span class="action-panel-label" id="fieldset-label"> Would you like email updates of new search results? </span> <fieldset id="saved-search-alert" aria-describedby="fieldset-label"> <legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend> <ul class="radio-group-items"> <li> <input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked> <label for="saved-search-alert-yes" class="action-panel-label">Yes</label> </li> <li> <input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no"> <label for="saved-search-alert-no" class="action-panel-label">No</label> </li> </ul> </fieldset> </div> <div class="alert-schedule-wrap"> <div class="action-panel-control-wrap"> <label class="action-panel-label"> Email: </label> <span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span> </div> <div class="action-panel-control-wrap action-panel-extra-margin-top"> <label for="saved-search-frequency" class="action-panel-label"> Frequency: </label> <select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency"> <option value="monthly">Monthly</option> <option value="weekly">Weekly</option> <option value="daily">Daily</option> </select> </div> <div class="action-panel-control-wrap saved-search-monthly-additional"> <label for="saved-search-monthly-on-day" class="action-panel-label"> Which day? </label> <select id="saved-search-monthly-on-day" class="no-border-panel-selector"> <option value="Sunday">The first Sunday</option> <option value="Monday">The first Monday</option> <option value="Tuesday">The first Tuesday</option> <option value="Wednesday">The first Wednesday</option> <option value="Thursday">The first Thursday</option> <option value="Friday">The first Friday</option> <option value="Saturday">The first Saturday</option> <option value="day">The first day</option> <option value="weekday">The first weekday</option> </select> </div> <div class="action-panel-control-wrap saved-search-weekly-additional"> <label for="saved-search-weekly-on-day" class="action-panel-label"> Which day? </label> <select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day"> <option value="Sunday">Sunday</option> <option value="Monday">Monday</option> <option value="Tuesday">Tuesday</option> <option value="Wednesday">Wednesday</option> <option value="Thursday">Thursday</option> <option value="Friday">Friday</option> <option value="Saturday">Saturday</option> </select> </div> <div class="action-panel-control-wrap"> <label for="saved-search-report" class="action-panel-label"> Report format: </label> <select id="saved-search-report" class="no-border-panel-selector saved-search-report"> <option value="DocSum">Summary</option> <option value="DocSumText">Summary (text)</option> <option value="Abstract">Abstract</option> <option value="AbstractText">Abstract (text)</option> <option value="MEDLINE">PubMed</option> </select> </div> <div class="action-panel-control-wrap"> <label for="saved-search-amount" class="action-panel-label"> Send at most: </label> <select id="saved-search-amount" class="no-border-panel-selector saved-search-amount"> <option value="1">1 item</option> <option value="5" selected>5 items</option> <option value="10">10 items</option> <option value="20">20 items</option> <option value="50">50 items</option> <option value="100">100 items</option> <option value="200">200 items</option> </select> </div> <div> <input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result"> <label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox"> Send even when there aren't any new results </label> </div> <div class="action-panel-control-wrap option-text-in-email-wrap"> <label for="saved-search-email-text" class="action-panel-label"> Optional text in email: </label> <textarea name="saved-search-email-text" id="saved-search-email-text" class="saved-search-email-text"></textarea> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Saving..." data-ga-category="save_share" data-ga-action="alert" data-ga-label="save"> Save </button> <button class="action-panel-cancel" aria-label="Close 'Your saved search' panel" ref="linksrc=close_saved_search_panel" aria-controls="saved-search-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="alert" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Create a file for external citation management software </h2> <form id="citation-manager-action-panel-form" class="action-panel-content action-form" action="/results-export-ids/" data-by-search-action="/results-export-search-data/" data-by-ids-action="/results-export-ids/" method="post" data-by-search-method="post" data-by-ids-method="post"> <input type="hidden" name="csrfmiddlewaretoken" value="WY7RoPgz7GN0tOJ7Vx2v6awyJUGrCoIkKU3S9an6pJPU0a1p0RX0CMmeqNTP2fr6"> <input name="results-format" type="hidden" value="pubmed"/> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Sending..." data-ga-category="save_share" data-ga-action="citation_manager" data-ga-label="save"> Create file </button> <button class="action-panel-cancel" aria-label="Close 'Send citations to citation manager' panel" ref="linksrc=close_citation_manager_panel" aria-controls="citation-manager-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="citation_manager" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Your RSS Feed </h2> <form id="rss-action-panel-form" class="rss-action-panel-form action-panel-content action-form" data-create-rss-feed-url="/create-rss-feed-url/" data-search-form-term-value=""> <input type="hidden" name="csrfmiddlewaretoken" value="WY7RoPgz7GN0tOJ7Vx2v6awyJUGrCoIkKU3S9an6pJPU0a1p0RX0CMmeqNTP2fr6"> <div class="action-panel-control-wrap"> <label for="rss-name" class="action-panel-label required-field-asterisk"> Name of RSS Feed: </label> <input maxlength="200" placeholder="Name" type="text" name="rss-name" id="rss-name" class="rss-name" value='' required pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"> </div> <div class="rss-limit-wrap"> <div class="action-panel-control-wrap action-panel-extra-margin-top"> <label for="rss-limit" class="action-panel-label"> Number of items displayed: </label> <select id="rss-limit" class="no-border-panel-selector rss-limit"> <option value="5">5</option> <option value="10">10</option> <option value="15" selected="selected">15</option> <option value="20">20</option> <option value="50">50</option> <option value="100">100</option> </select> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Creating..." data-ga-category="save_share" data-ga-action="alert" data-ga-label="save"> Create RSS </button> <button class="action-panel-cancel" aria-label="Close 'Your RSS' panel" ref="linksrc=close_rss_panel" aria-controls="rss-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="alert" data-ga-label="cancel"> Cancel </button> </div> <div class="action-panel-control-wrap rss-link-copy-wrap"> <label for="rss-link" class="usa-sr-only">RSS Link</label> <input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link"> <button type="button" disabled class="rss-link-copy-button disabled" data-ga-category="save_share" data-ga-action="rss" data-ga-label="copy"> Copy </button> </div> </form> </div> </div> </div> </div> <div class="article-page" id="article-page" data-article-pmid="38232291"> <aside class="page-sidebar"> <div class="inner-wrap"> <div class="full-text-links"> <div class="full-view"> <h3 class="title"> Full text links </h3> <div class="full-text-links-list"> <a class="link-item dialog-focus" 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required-field-asterisk"> Name your collection: </label><input type="text" name="add-to-new-collection" id="collections-action-dialog-add-to-new" class="collections-action-add-to-new" pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/" maxlength="100" data-ga-category="collections_button" data-ga-action="create_collection" data-ga-label="non_favorties_collection"><div class="collections-new-name-too-long usa-input-error-message selection-validation-message"> Name must be less than 100 characters </div></div><div class="action-panel-control-wrap existing-collections-controls"><label for="collections-action-dialog-add-to-existing" class="action-panel-label"> Choose a collection: </label><select id="collections-action-dialog-add-to-existing" class="action-panel-selector collections-action-add-to-existing" data-ga-category="collections_button" data-ga-action="select_collection" data-ga-label="($('.collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'"></select><div class="collections-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your collection due to an error<br><a href="#">Please try again</a></div></div></div><div class="action-panel-actions"><button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore data-ga-category="collections_button" data-ga-action="click" data-ga-label="add"> Add </button><button class="action-panel-cancel" aria-label="Close 'Add to Collections' panel" ref="linksrc=close_collections_panel" aria-controls="collections-action-panel" aria-expanded="false" data-ga-category="collections_button" data-ga-action="click" data-ga-label="cancel"> Cancel </button></div></form></div></div></div></div><button class="more-actions-button more-actions-dialog-trigger" title="Open dialog with more actions to take" ref="linksrc=more_actions_btn"></button><div class="display-options" 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aria-expanded="false" aria-label="Toggle dropdown menu for journal Proceedings of the National Academy of Sciences of the United States of America" data-pinger-ignore> Proc Natl Acad Sci U S A </button><div id="full-view-journal" class="journal-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for journal Proceedings of the National Academy of Sciences of the United States of America"><div class="title">Actions</div><div class="content"><ul class="journal-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Proc+Natl+Acad+Sci+U+S+A%22%5Bjour%5D&sort=date&sort_order=desc" data-href="/?term=%22Proc+Natl+Acad+Sci+U+S+A%22%5Bjour%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_journal_name_link&journal_abbrev=Proc Natl Acad Sci U S A" data-ga-category="search" data-ga-action="journal_link" data-ga-label="Proc Natl Acad Sci U S A"> Search in PubMed </a></li><li><a class="search-in-nlm-catalog-link dropdown-block-link" ref ="linksrc=search_in_nlm_catalog_link" href="https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Proc+Natl+Acad+Sci+U+S+A%22%5BTitle+Abbreviation%5D" data-ga-category="search_catalog" data-ga-action="journal_link" data-ga-label="Proc Natl Acad Sci U S A"> Search in NLM Catalog </a></li><li><a class="add-to-search-link dropdown-block-link" ref ="linksrc=add_to_search_link" role="button" data-search-term='"Proc Natl Acad Sci U S A"[jour]' data-ga-category="search" data-ga-action="add_to_search" data-ga-label='"Proc Natl Acad Sci U S A"[jour]' href="#"> Add to Search </a></li></ul></div></div></div><span class="period">. </span><span class="cit">2024 Jan 23;121(4):e2318093121.</span> </div> <span class="citation-doi"> doi: 10.1073/pnas.2318093121. </span> <span class="secondary-date"> Epub 2024 Jan 17. </span> </div> <h1 class="heading-title"> A second-generation eIF4A RNA helicase inhibitor exploits translational reprogramming as a vulnerability in triple-negative breast cancer </h1> <div class="inline-authors"> <div class="authors"> <div class="authors-list"> <span class="authors-list-item "><a class="full-name" href="/?term=Cencic+R&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Regina Cencic">Regina Cencic</a><sup class="equal-contrib-container"><span class="author-sup-separator"> </span><a class="equal-contrib" title="Contributed equally" href="#full-view-equal-contrib-explanation" ref="linksrc=author_equal_contrib">#</a></sup><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada." href="#full-view-affiliation-2" ref="linksrc=author_aff"> 2 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Im+YK&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Young K Im">Young K Im</a><sup class="equal-contrib-container"><span class="author-sup-separator"> </span><a class="equal-contrib" title="Contributed equally" href="#full-view-equal-contrib-explanation" ref="linksrc=author_equal_contrib">#</a></sup><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Lady Davis Institute for Medical Research, Montreal, QC H3T 1E2, Canada." href="#full-view-affiliation-3" ref="linksrc=author_aff"> 3 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Naineni+SK&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Sai Kiran Naineni">Sai Kiran Naineni</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada." href="#full-view-affiliation-2" ref="linksrc=author_aff"> 2 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Moustafa-Kamal+M&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Mohamed Moustafa-Kamal">Mohamed Moustafa-Kamal</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada." href="#full-view-affiliation-2" ref="linksrc=author_aff"> 2 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Jovanovic+P&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Predrag Jovanovic">Predrag Jovanovic</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Lady Davis Institute for Medical Research, Montreal, QC H3T 1E2, Canada." href="#full-view-affiliation-3" ref="linksrc=author_aff"> 3 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada." href="#full-view-affiliation-4" ref="linksrc=author_aff"> 4 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Sabourin+V&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Valerie Sabourin">Valerie Sabourin</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Lady Davis Institute for Medical Research, Montreal, QC H3T 1E2, Canada." href="#full-view-affiliation-3" ref="linksrc=author_aff"> 3 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Annis+MG&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Matthew G Annis">Matthew G Annis</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada." href="#full-view-affiliation-2" ref="linksrc=author_aff"> 2 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Robert+F&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Francis Robert">Francis Robert</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada." href="#full-view-affiliation-2" ref="linksrc=author_aff"> 2 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Schmeing+TM&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="T Martin Schmeing">T Martin Schmeing</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada." href="#full-view-affiliation-2" ref="linksrc=author_aff"> 2 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Koromilas+A&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Antonis Koromilas">Antonis Koromilas</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Lady Davis Institute for Medical Research, Montreal, QC H3T 1E2, Canada." href="#full-view-affiliation-3" ref="linksrc=author_aff"> 3 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada." href="#full-view-affiliation-4" ref="linksrc=author_aff"> 4 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H4A 3T2, Canada." href="#full-view-affiliation-5" ref="linksrc=author_aff"> 5 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Paquet+M&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Marilène Paquet">Marilène Paquet</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Département de pathologie et de microbiologie, Faculté de médecine vétérinaire, Université de Montréal, Montréal, QC H3C 3J7, Canada." href="#full-view-affiliation-6" ref="linksrc=author_aff"> 6 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Teodoro+JG&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Jose G Teodoro">Jose G Teodoro</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada." href="#full-view-affiliation-2" ref="linksrc=author_aff"> 2 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Huang+S&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Sidong Huang">Sidong Huang</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada." href="#full-view-affiliation-2" ref="linksrc=author_aff"> 2 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Siegel+PM&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Peter M Siegel">Peter M Siegel</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada." href="#full-view-affiliation-2" ref="linksrc=author_aff"> 2 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada." href="#full-view-affiliation-4" ref="linksrc=author_aff"> 4 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H4A 3T2, Canada." href="#full-view-affiliation-5" ref="linksrc=author_aff"> 5 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada." href="#full-view-affiliation-7" ref="linksrc=author_aff"> 7 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Topisirovic+I&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Ivan Topisirovic">Ivan Topisirovic</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Lady Davis Institute for Medical Research, Montreal, QC H3T 1E2, Canada." href="#full-view-affiliation-3" ref="linksrc=author_aff"> 3 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada." href="#full-view-affiliation-4" ref="linksrc=author_aff"> 4 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H4A 3T2, Canada." href="#full-view-affiliation-5" ref="linksrc=author_aff"> 5 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Ursini-Siegel+J&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Josie Ursini-Siegel">Josie Ursini-Siegel</a><sup class="equal-contrib-container"><span class="author-sup-separator"> </span><a class="equal-contrib" title="Contributed equally" href="#full-view-equal-contrib-explanation" ref="linksrc=author_equal_contrib">#</a></sup><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Lady Davis Institute for Medical Research, Montreal, QC H3T 1E2, Canada." href="#full-view-affiliation-3" ref="linksrc=author_aff"> 3 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada." href="#full-view-affiliation-4" ref="linksrc=author_aff"> 4 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H4A 3T2, Canada." href="#full-view-affiliation-5" ref="linksrc=author_aff"> 5 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Pelletier+J&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Jerry Pelletier">Jerry Pelletier</a><sup class="equal-contrib-container"><span class="author-sup-separator"> </span><a class="equal-contrib" title="Contributed equally" href="#full-view-equal-contrib-explanation" ref="linksrc=author_equal_contrib">#</a></sup><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada." href="#full-view-affiliation-2" ref="linksrc=author_aff"> 2 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada." href="#full-view-affiliation-4" ref="linksrc=author_aff"> 4 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H4A 3T2, Canada." href="#full-view-affiliation-5" ref="linksrc=author_aff"> 5 </a></sup></span> </div> </div> </div> <div class="short-article-details"> Affiliations <button class="more-details" id="toggle-authors" data-alt-text="Collapse" aria-controls="expanded-authors" aria-expanded="false" data-pinger-ignore data-fetch-url="/38232291/long-authors/" data-id-prefix=""> <span class="title"> Expand </span> </button> </div> <div class="extended-article-details" id="expanded-authors" aria-hidden="true"> <div class="expanded-authors" id="full-view-expanded-authors"> <div class="affiliations"> <h3 class="title"> Affiliations </h3> <ul class="item-list"> <li data-affiliation-id="full-view-affiliation-1" id="full-view-affiliation-1" ><sup class="key">1</sup> Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.</li> <li data-affiliation-id="full-view-affiliation-2" id="full-view-affiliation-2" ><sup class="key">2</sup> Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada.</li> <li data-affiliation-id="full-view-affiliation-3" id="full-view-affiliation-3" ><sup class="key">3</sup> Lady Davis Institute for Medical Research, Montreal, QC H3T 1E2, Canada.</li> <li data-affiliation-id="full-view-affiliation-4" id="full-view-affiliation-4" ><sup class="key">4</sup> Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada.</li> <li data-affiliation-id="full-view-affiliation-5" id="full-view-affiliation-5" ><sup class="key">5</sup> Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H4A 3T2, Canada.</li> <li data-affiliation-id="full-view-affiliation-6" id="full-view-affiliation-6" ><sup class="key">6</sup> Département de pathologie et de microbiologie, Faculté de médecine vétérinaire, Université de Montréal, Montréal, QC H3C 3J7, Canada.</li> <li data-affiliation-id="full-view-affiliation-7" id="full-view-affiliation-7" ><sup class="key">7</sup> Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada.</li> </ul> </div> <div class="equal-contrib-block"> <div class="equal-contrib-explanation" id="full-view-equal-contrib-explanation"><sup class="key">#</sup> Contributed equally.</div> </div> </div> </div> <ul class="identifiers" id="full-view-identifiers"> <li> <span class="identifier pubmed"> <span class="id-label"> PMID: </span> <strong class="current-id" title="PubMed ID">38232291</strong> </span> </li> <li> <span class="identifier pmc"> <span class="id-label"> PMCID: </span> <a class="id-link" target="_blank" rel="noopener" ref="linksrc=article_id_link&article_id=PMC10823175&id_type=PMC" href="https://pmc.ncbi.nlm.nih.gov/articles/PMC10823175/" data-ga-category="full_text" data-ga-action="PMCID" > PMC10823175 </a> </span> </li> <li> <span class="identifier doi"> <span class="id-label"> DOI: </span> <a class="id-link" target="_blank" rel="noopener" ref="linksrc=article_id_link&article_id=10.1073/pnas.2318093121&id_type=DOI" href="https://doi.org/10.1073/pnas.2318093121" data-ga-category="full_text" data-ga-action="DOI" > 10.1073/pnas.2318093121 </a> </span> </li> </ul> <div class="in-clipboard-label " hidden> Item in Clipboard </div> </div> <div class="short-view" id="short-view-heading"> <h1 class="heading-title"> A second-generation eIF4A RNA helicase inhibitor exploits translational reprogramming as a vulnerability in triple-negative breast cancer </h1> <div class="short-citation"> <span class="authors-list"> <span class="authors-list-item "><span class="full-name">Regina Cencic</span><span class="citation-separator"> et al.</span></span> </span> <span class="citation-journal"> Proc Natl Acad Sci U S A<span class="citation-separator">.</span> </span> <span class="date"> <time class="citation-year" datetime="2024">2024</time><span class="citation-separator">.</span> </span> </div> <div class="more-article-details-section with-display-settings"> <button class="more-article-details" id="toggle-article-details" data-alt-text="Hide details" ref="linksrc=toggle_article_details" aria-controls="full-article-details" aria-expanded="false" data-fetch-url="/38232291/long-authors/" data-id-prefix=""> <span class="title">Show details</span> </button> <div class="display-options" data-format-key="format" data-default-format-value="abstract" data-current-format-value="abstract" role="region"> <button class="trigger usa-button" title="Change format" data-ga-category="display_options" data-ga-action="display_options_dialog"> <span class="button-label">Display options</span> </button> <div class="dropdown" hidden> <div class="title"> Display options </div> <div class="content"> <div class="format-container"> <span class="option-label"> Format </span> <select name="format" data-initial-value="abstract" aria-label="Display format" id="mobile-display-format"> <option value="abstract">Abstract</option> <option value="pubmed">PubMed</option> <option value="pmid">PMID</option> </select> </div> </div> </div> </div> </div> <div class="extended-article-details" id="full-article-details" aria-hidden="true"> <div class="article-citation"> <div class="article-source"> <div class="journal-actions dropdown-block"><button id="short-view-journal-trigger" class="journal-actions-trigger trigger" ref="linksrc=journal_actions_btn" title="Proceedings of the National Academy of Sciences of the United States of America" tabindex="0" aria-controls="short-view-journal" aria-expanded="false" aria-label="Toggle dropdown menu for journal Proceedings of the National Academy of Sciences of the United States of America" data-pinger-ignore> Proc Natl Acad Sci U S A </button><div id="short-view-journal" class="journal-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for journal Proceedings of the National Academy of Sciences of the United States of America"><div class="title">Actions</div><div class="content"><ul class="journal-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Proc+Natl+Acad+Sci+U+S+A%22%5Bjour%5D&sort=date&sort_order=desc" data-href="/?term=%22Proc+Natl+Acad+Sci+U+S+A%22%5Bjour%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_journal_name_link&journal_abbrev=Proc Natl Acad Sci U S A" data-ga-category="search" data-ga-action="journal_link" data-ga-label="Proc Natl Acad Sci U S A"> Search in PubMed </a></li><li><a class="search-in-nlm-catalog-link dropdown-block-link" ref ="linksrc=search_in_nlm_catalog_link" href="https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Proc+Natl+Acad+Sci+U+S+A%22%5BTitle+Abbreviation%5D" data-ga-category="search_catalog" data-ga-action="journal_link" data-ga-label="Proc Natl Acad Sci U S A"> Search in NLM Catalog </a></li><li><a class="add-to-search-link dropdown-block-link" ref ="linksrc=add_to_search_link" role="button" data-search-term='"Proc Natl Acad Sci U S A"[jour]' data-ga-category="search" data-ga-action="add_to_search" data-ga-label='"Proc Natl Acad Sci U S A"[jour]' href="#"> Add to Search </a></li></ul></div></div></div><span class="period">. </span><span class="cit">2024 Jan 23;121(4):e2318093121.</span> </div> <span class="citation-doi"> doi: 10.1073/pnas.2318093121. </span> <span class="secondary-date"> Epub 2024 Jan 17. </span> </div> <div class="expanded-authors" id="short-view-expanded-authors"> <div class="authors"> <h3 class="title"> Authors </h3> <div class="authors-list"> <span class="authors-list-item "><a class="full-name" href="/?term=Cencic+R&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Regina Cencic">Regina Cencic</a><sup class="equal-contrib-container"><span class="author-sup-separator"> </span><a class="equal-contrib" title="Contributed equally" href="#short-view-equal-contrib-explanation" ref="linksrc=author_equal_contrib">#</a></sup><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada." href="#short-view-affiliation-2" ref="linksrc=author_aff"> 2 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Im+YK&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Young K Im">Young K Im</a><sup class="equal-contrib-container"><span class="author-sup-separator"> </span><a class="equal-contrib" title="Contributed equally" href="#short-view-equal-contrib-explanation" ref="linksrc=author_equal_contrib">#</a></sup><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Lady Davis Institute for Medical Research, Montreal, QC H3T 1E2, Canada." href="#short-view-affiliation-3" ref="linksrc=author_aff"> 3 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Naineni+SK&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Sai Kiran Naineni">Sai Kiran Naineni</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada." href="#short-view-affiliation-2" ref="linksrc=author_aff"> 2 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Moustafa-Kamal+M&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Mohamed Moustafa-Kamal">Mohamed Moustafa-Kamal</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada." href="#short-view-affiliation-2" ref="linksrc=author_aff"> 2 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Jovanovic+P&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Predrag Jovanovic">Predrag Jovanovic</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Lady Davis Institute for Medical Research, Montreal, QC H3T 1E2, Canada." href="#short-view-affiliation-3" ref="linksrc=author_aff"> 3 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada." href="#short-view-affiliation-4" ref="linksrc=author_aff"> 4 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Sabourin+V&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Valerie Sabourin">Valerie Sabourin</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Lady Davis Institute for Medical Research, Montreal, QC H3T 1E2, Canada." href="#short-view-affiliation-3" ref="linksrc=author_aff"> 3 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Annis+MG&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Matthew G Annis">Matthew G Annis</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada." href="#short-view-affiliation-2" ref="linksrc=author_aff"> 2 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Robert+F&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Francis Robert">Francis Robert</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada." href="#short-view-affiliation-2" ref="linksrc=author_aff"> 2 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Schmeing+TM&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="T Martin Schmeing">T Martin Schmeing</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada." href="#short-view-affiliation-2" ref="linksrc=author_aff"> 2 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Koromilas+A&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Antonis Koromilas">Antonis Koromilas</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Lady Davis Institute for Medical Research, Montreal, QC H3T 1E2, Canada." href="#short-view-affiliation-3" ref="linksrc=author_aff"> 3 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada." href="#short-view-affiliation-4" ref="linksrc=author_aff"> 4 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H4A 3T2, Canada." href="#short-view-affiliation-5" ref="linksrc=author_aff"> 5 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Paquet+M&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Marilène Paquet">Marilène Paquet</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Département de pathologie et de microbiologie, Faculté de médecine vétérinaire, Université de Montréal, Montréal, QC H3C 3J7, Canada." href="#short-view-affiliation-6" ref="linksrc=author_aff"> 6 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Teodoro+JG&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Jose G Teodoro">Jose G Teodoro</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada." href="#short-view-affiliation-2" ref="linksrc=author_aff"> 2 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Huang+S&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Sidong Huang">Sidong Huang</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada." href="#short-view-affiliation-2" ref="linksrc=author_aff"> 2 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Siegel+PM&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Peter M Siegel">Peter M Siegel</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada." href="#short-view-affiliation-2" ref="linksrc=author_aff"> 2 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada." href="#short-view-affiliation-4" ref="linksrc=author_aff"> 4 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H4A 3T2, Canada." href="#short-view-affiliation-5" ref="linksrc=author_aff"> 5 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada." href="#short-view-affiliation-7" ref="linksrc=author_aff"> 7 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Topisirovic+I&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Ivan Topisirovic">Ivan Topisirovic</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Lady Davis Institute for Medical Research, Montreal, QC H3T 1E2, Canada." href="#short-view-affiliation-3" ref="linksrc=author_aff"> 3 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada." href="#short-view-affiliation-4" ref="linksrc=author_aff"> 4 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H4A 3T2, Canada." href="#short-view-affiliation-5" ref="linksrc=author_aff"> 5 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Ursini-Siegel+J&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Josie Ursini-Siegel">Josie Ursini-Siegel</a><sup class="equal-contrib-container"><span class="author-sup-separator"> </span><a class="equal-contrib" title="Contributed equally" href="#short-view-equal-contrib-explanation" ref="linksrc=author_equal_contrib">#</a></sup><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Lady Davis Institute for Medical Research, Montreal, QC H3T 1E2, Canada." href="#short-view-affiliation-3" ref="linksrc=author_aff"> 3 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada." href="#short-view-affiliation-4" ref="linksrc=author_aff"> 4 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H4A 3T2, Canada." href="#short-view-affiliation-5" ref="linksrc=author_aff"> 5 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Pelletier+J&cauthor_id=38232291" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Jerry Pelletier">Jerry Pelletier</a><sup class="equal-contrib-container"><span class="author-sup-separator"> </span><a class="equal-contrib" title="Contributed equally" href="#short-view-equal-contrib-explanation" ref="linksrc=author_equal_contrib">#</a></sup><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada." href="#short-view-affiliation-2" ref="linksrc=author_aff"> 2 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada." href="#short-view-affiliation-4" ref="linksrc=author_aff"> 4 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H4A 3T2, Canada." href="#short-view-affiliation-5" ref="linksrc=author_aff"> 5 </a></sup></span> </div> </div> <div class="affiliations"> <h3 class="title"> Affiliations </h3> <ul class="item-list"> <li data-affiliation-id="short-view-affiliation-1" id="short-view-affiliation-1" ><sup class="key">1</sup> Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.</li> <li data-affiliation-id="short-view-affiliation-2" id="short-view-affiliation-2" ><sup class="key">2</sup> Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada.</li> <li data-affiliation-id="short-view-affiliation-3" id="short-view-affiliation-3" ><sup class="key">3</sup> Lady Davis Institute for Medical Research, Montreal, QC H3T 1E2, Canada.</li> <li data-affiliation-id="short-view-affiliation-4" id="short-view-affiliation-4" ><sup class="key">4</sup> Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada.</li> <li data-affiliation-id="short-view-affiliation-5" id="short-view-affiliation-5" ><sup class="key">5</sup> Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H4A 3T2, Canada.</li> <li data-affiliation-id="short-view-affiliation-6" id="short-view-affiliation-6" ><sup class="key">6</sup> Département de pathologie et de microbiologie, Faculté de médecine vétérinaire, Université de Montréal, Montréal, QC H3C 3J7, Canada.</li> <li data-affiliation-id="short-view-affiliation-7" id="short-view-affiliation-7" ><sup class="key">7</sup> Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada.</li> </ul> </div> <div class="equal-contrib-block"> <div class="equal-contrib-explanation" id="short-view-equal-contrib-explanation"><sup class="key">#</sup> Contributed equally.</div> </div> </div> <ul class="identifiers" id="short-view-identifiers"> <li> <span class="identifier pubmed"> <span class="id-label"> PMID: </span> <strong class="current-id" title="PubMed ID">38232291</strong> </span> </li> <li> <span class="identifier pmc"> <span class="id-label"> PMCID: </span> <a class="id-link" target="_blank" rel="noopener" ref="linksrc=article_id_link&article_id=PMC10823175&id_type=PMC" href="https://pmc.ncbi.nlm.nih.gov/articles/PMC10823175/" data-ga-category="full_text" data-ga-action="PMCID" > PMC10823175 </a> </span> </li> <li> <span class="identifier doi"> <span class="id-label"> DOI: </span> <a class="id-link" target="_blank" rel="noopener" ref="linksrc=article_id_link&article_id=10.1073/pnas.2318093121&id_type=DOI" href="https://doi.org/10.1073/pnas.2318093121" data-ga-category="full_text" data-ga-action="DOI" > 10.1073/pnas.2318093121 </a> </span> </li> </ul> <div class="in-clipboard-label " hidden> Item in Clipboard </div> </div> </div> </header> <div class="actions-buttons inline"><div class="inner-wrap"><button class="full-text-links-button full-text-links-dialog-trigger" title="Open dialog with full text links" ref="linksrc=full_text_links"> Full text links </button><button class="citation-button citation-dialog-trigger" aria-label="Open dialog with citation text in different styles" data-ga-category="save_share" data-ga-action="cite" data-ga-label="open" data-all-citations-url="/38232291/citations/" data-citation-style="nlm" data-pubmed-format-link="/38232291/export/"><span class="button-label">Cite</span></button><button class="more-actions-button more-actions-dialog-trigger" title="Open dialog with more actions to take" ref="linksrc=more_actions_btn"></button><div class="display-options" data-format-key="format" data-default-format-value="abstract" data-current-format-value="abstract" role="region"><button class="trigger usa-button" title="Change format" data-ga-category="display_options" data-ga-action="display_options_dialog"><span class="button-label">Display options</span></button><div class="dropdown" hidden><div class="title"> Display options </div><div class="content"><div class="format-container"><span class="option-label"> Format </span><select name="format" data-initial-value="abstract" aria-label="Display format" id="inline-actions-display-format"><option value="abstract">Abstract</option><option value="pubmed">PubMed</option><option value="pmid">PMID</option></select></div></div></div></div></div></div> <div class="abstract" id="abstract"> <h2 class="title"> Abstract </h2> <div class="abstract-content selected" id="eng-abstract"> <p> In this study, we aimed to address the current limitations of therapies for macro-metastatic triple-negative breast cancer (TNBC) and provide a therapeutic lead that overcomes the high degree of heterogeneity associated with this disease. Specifically, we focused on well-documented but clinically underexploited cancer-fueling perturbations in mRNA translation as a potential therapeutic vulnerability. We therefore developed an orally bioavailable rocaglate-based molecule, MG-002, which hinders ribosome recruitment and scanning via unscheduled and non-productive RNA clamping by the eukaryotic translation initiation factor (eIF) 4A RNA helicase. We demonstrate that MG-002 potently inhibits mRNA translation and primary TNBC tumor growth without causing overt toxicity in mice. Importantly, given that metastatic spread is a major cause of mortality in TNBC, we show that MG-002 attenuates metastasis in pre-clinical models. We report on MG-002, a rocaglate that shows superior properties relative to existing eIF4A inhibitors in pre-clinical models. Our study also paves the way for future clinical trials exploring the potential of MG-002 in TNBC and other oncological indications. </p> </div> <p> <strong class="sub-title"> Keywords: </strong> eIF4A; lung metastasis; mRNA translation; triple-negative breast cancer. </p> </div> <p class="disclaimer" id="disclaimer"> <a href="/disclaimer/" target="_blank" ga_category="literature_resources" ga_action="disclaimer_link" ga_label="under_abstract">PubMed Disclaimer</a> </p> <div class="conflict-of-interest" id="conflict-of-interest"> <h2 class="title"> Conflict of interest statement </h2> <div class="statement"> <p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Competing interests statement:The authors declare no competing interest.</p> </div> </div> <div class="figures" id="figures"> <h2 class="title"> Figures </h2> <div class="figures-list" id="slides-container" itemscope itemtype="http://schema.org/ImageGallery"> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="0" data-label-slug="fig-1"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a776/10823175/97b40d17bb9a/pnas.2318093121fig01.jpg" itemprop="contentUrl" aria-describedby="figure-caption-0" role="button" data-image-width="4017" data-image-height="3155" data-image-alt="Fig. 1." data-pmc-id="PMC10823175" data-figure-id="fig01"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-0" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a776/10823175/478aaddf7282/pnas.2318093121fig01.gif" alt="Fig. 1." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="4017"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="3155"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Fig. 1. </p> </strong> <div class="figure-caption-contents"><p> Design of an eIF4A inhibitor… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Fig. 1. </p> </strong> <div class="figure-caption-contents"><p> Design of an eIF4A inhibitor (MG-002) that potently inhibits cap-dependent mRNA translation. (… </p></div> </div> <figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Fig. 1. </strong> <div class="figure-caption-contents">Design of an eIF4A inhibitor (MG-002) that potently inhibits cap-dependent mRNA translation. (<i>A</i>) Schematic outlining the rationale behind MG-002 development. RNA- (blue shading) and eIF4A1 (green shading)-interacting regions are highlighted on the RocA structure. Insets show close in views of a model of the MG-002 hydroxymate and nitrile groups, based on the RocA-bound crystal structure of eIF4A1 (26). (<i>B</i>) Assessing compound-induced clamping of eIF4A1 to FAM-labeled RNA of the indicated nucleotide composition by fluorescence polarization assay. The ΔmP (change in polarization) obtained with eIF4A1•AMPPNP •poly (NN)<sub>8</sub> RNA was measured for the indicated compounds at 10 µM. The ΔmP obtained relative to dimethylsulfoxide (DMSO) is shown (n = 3 ±SD). (<i>C</i>) Relative dissociation of pre-formed eIF4A1•ATP•Cmpd•FAM-poly (AG)<sub>8</sub> complexes measured as a function of time in the presence of 1,000-fold molar excess poly (AG)<sub>8</sub> RNA. DMSO, t<sub>1/2</sub> ~4.1 ± 1 min; CR-1-31B (10 µM), t<sub>1/2</sub> ~59 ± 6.5 min; MG-002 (10 µM), t<sub>1/2</sub> ~68 ± 2.8 min; eFT226 (10 µM), t<sub>1/2</sub> ~ 27 ± 5.8 min. Error values were calculated from the 95% CI. (<i>D</i>) Differential scanning fluorimetry analysis of eIF4A1 (8 µM) in the presence of the indicated compounds (15 µM), 15 µM poly (AG)<sub>8</sub>, and 1 mM AMPPNP. The transition midpoint temperature shifts (ΔT<sub>50</sub>) are: CR-1-31B, 7.3 °C; eFT226, 7 °C; MG-002, 7.2 °C; PatA, 10 °C (n = 3 ±SD). (<i>E</i>) Inhibition of cap-dependent (FLuc) and independent (RLuc) translation was measured in response to the indicated compounds in Krebs-2 translation extracts programmed with the noted bicistronic mRNA. IC<sub>50</sub>s toward inhibition of FLuc synthesis from (CAG)-FF/HCV-IRES/Ren mRNA were: CR-1-31B, 54 ± 4 nM; eFT226, 813 ± 91 nM; MG-002, 43 ± 4 nM (n = 2 ±SD). (<i>F</i>) eHap1 cells were incubated in the presence of the indicated concentrations of compound for 1 h. During the last 15 min of incubation, <sup>35</sup>S-Met was added followed by TCA precipitation and quantitation of <sup>35</sup>S-Met incorporation into protein (n = 3 ±SD).</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="1" data-label-slug="fig-2"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a776/10823175/25e9e4a6fd4a/pnas.2318093121fig02.jpg" itemprop="contentUrl" aria-describedby="figure-caption-1" role="button" data-image-width="4016" data-image-height="1781" data-image-alt="Fig. 2." data-pmc-id="PMC10823175" data-figure-id="fig02"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-1" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a776/10823175/2525fa7f31c8/pnas.2318093121fig02.gif" alt="Fig. 2." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="4016"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="1781"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Fig. 2. </p> </strong> <div class="figure-caption-contents"><p> MG-002 significantly and selectively impairs… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Fig. 2. </p> </strong> <div class="figure-caption-contents"><p> MG-002 significantly and selectively impairs breast cancer cell growth and viability. ( <i> A… </i> </p></div> </div> <figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Fig. 2. </strong> <div class="figure-caption-contents">MG-002 significantly and selectively impairs breast cancer cell growth and viability. (<i>A</i>) Time of MDA-MB-231 cells to enter mitosis following release from DNA synthesis block. Release was performed in the presence of DMSO or 10 nM of the indicated compounds. The data shows the average of 50 cells ±SD. (<i>B</i>) Activity of CR-1-31B, eFT226, and MG-002 toward three TNBC cells lines (4T1, BT474, MDA-MB-231). Cells were exposed to the indicated concentrations of compound for 2 d (except for BT474 cells where exposure was for 4 d) and viability measured using the SRB assay. n = 3 ±SD. (<i>C</i>) Activity of CR-1-31B, eFT226, and MG-002 toward IMR-90 and MRC-5 immortalized and non-transformed cells. Cells were exposed to the indicated concentrations of compound for 2 d and stained with SRB. n = 3 ±SD. (<i>D</i>) Activity of CR-1-31B, eFT226, and MG-002 toward HUVEC cell line. Cells were exposed to the indicated concentrations of compound for 2 d and then stained with SRB. n = 3 ±SD. (<i>E</i>) Western blot analysis of the indicated proteins in cells exposed to MG-002 (100 nM), CR-1-31B (100 nM), or doxorubicin (DXR, 0.5 µg/mL) for 24 h.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="2" data-label-slug="fig-3"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a776/10823175/4e50eee73e9f/pnas.2318093121fig03.jpg" itemprop="contentUrl" aria-describedby="figure-caption-2" role="button" data-image-width="4016" data-image-height="3169" data-image-alt="Fig. 3." data-pmc-id="PMC10823175" data-figure-id="fig03"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-2" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a776/10823175/5b4ac31b36ca/pnas.2318093121fig03.gif" alt="Fig. 3." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="4016"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="3169"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Fig. 3. </p> </strong> <div class="figure-caption-contents"><p> eIF4A is the molecular target… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Fig. 3. </p> </strong> <div class="figure-caption-contents"><p> eIF4A is the molecular target for MG-002. ( <i> A </i> ) Activity of MG-002… </p></div> </div> <figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Fig. 3. </strong> <div class="figure-caption-contents">eIF4A is the molecular target for MG-002. (<i>A</i>) Activity of MG-002 toward parental eHAP1 or eIF4A1<sup>F163L</sup>/eIF4A2<sup>−</sup> cells. (<i>B</i>) Rocaglate-induced clamping of eIF4A1 to mRNAs leads to inhibition of translation and cell death. In contrast, eIF4A1<sup>F163L</sup>/eIF4A2<sup>−</sup> eHAP1 cells are significantly resistant to rocaglates as clamping of eIF4A1<sup>F163L</sup> to RNA is impaired. Overexpression of wt eIF4A1 in eIF4A1<sup>F163L</sup>/eIF4A2<sup>−</sup> cells restores rocaglate-induced translation inhibition and cell death. (<i>C</i>) Immunoblot of the indicated proteins from cell lines ectopically expressing V5 tagged eIF4A1, eIF4A2, or untagged DDX3X. (<i>D</i>) Cytotoxicity of eIF4A1<sup>F163L</sup>/eIF4A2<sup>−</sup> eHAP1 cells ectopically expressing GFP, eIF4A1, eIF4A2, or DDX3X following a 2-d exposure to the indicated MG-002 concentrations (n = 3 ±SD). (<i>E</i>) Response of eHAP1 cells ectopically expressing GFP, eIF4A1, eIF4A2, or DDX3X following a 2-d exposure to the indicated MG-002 concentrations (n = 3 ±SD). (<i>F</i>) Cytotoxicity of eHAP1 or eIF4A1<sup>F163L</sup>/eIF4A2<sup>−</sup> cells ectopically expressing eIF4A1<sup>F163L</sup> following a 2-d exposure to the indicated MG-002 concentrations (n = 3 ±SD).</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="3" data-label-slug="fig-4"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a776/10823175/4db4a572808c/pnas.2318093121fig04.jpg" itemprop="contentUrl" aria-describedby="figure-caption-3" role="button" data-image-width="792" data-image-height="1124" data-image-alt="Fig. 4." data-pmc-id="PMC10823175" data-figure-id="fig04"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-3" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a776/10823175/5387ffdd78f9/pnas.2318093121fig04.gif" alt="Fig. 4." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="792"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="1124"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Fig. 4. </p> </strong> <div class="figure-caption-contents"><p> MG-002 accumulates in biological tissues… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Fig. 4. </p> </strong> <div class="figure-caption-contents"><p> MG-002 accumulates in biological tissues and has minimal toxicities. ( <i> A </i> ) Average… </p></div> </div> <figcaption id="figure-caption-3" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Fig. 4. </strong> <div class="figure-caption-contents">MG-002 accumulates in biological tissues and has minimal toxicities. (<i>A</i>) Average plasma concentration of MG-002 at the indicated time points following compound delivery by intravenous (IV) versus oral gavage (PO). (<i>B</i>) Polysomes isolated from livers of mice treated with vehicle or at the indicated time points following delivery of 0.5 mg/kg MG-002 PO. Polysome/monosome (P/M) ratio represents the average of two experiments. (<i>C</i>) Quantification of the P/M ratios shown in panel <i>B</i>. (<i>D</i>) Concentration of MG-002 in the indicated tissues 4 h after PO delivery of MG-002 (5 mg/kg) (n = 3 ±SD). (<i>E</i>) Total blood cell counts (total leukocytes, neutrophils, lymphocytes, monocytes, or eosinophils) from mice treated with vehicle or 0.5 mg/kg MG-002 PO on Mon/Wed/Fri for two consecutive weeks (n = 4 to 5 ±SD). (<i>F</i>) Tissue weights from mice treated with vehicle or 0.5 mg/kg MG-002 PO Mon/Wed/Fri for two consecutive weeks, after which time organs were harvested (n = 4 to 5 ±SD).</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="4" data-label-slug="fig-5"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a776/10823175/963506442e90/pnas.2318093121fig05.jpg" itemprop="contentUrl" aria-describedby="figure-caption-4" role="button" data-image-width="3780" data-image-height="1991" data-image-alt="Fig. 5." data-pmc-id="PMC10823175" data-figure-id="fig05"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-4" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a776/10823175/fce4d4c42643/pnas.2318093121fig05.gif" alt="Fig. 5." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="3780"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="1991"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Fig. 5. </p> </strong> <div class="figure-caption-contents"><p> MG-002 inhibits primary TNBC tumor… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Fig. 5. </p> </strong> <div class="figure-caption-contents"><p> MG-002 inhibits primary TNBC tumor growth through reduced cell proliferation and increased apoptosis.… </p></div> </div> <figcaption id="figure-caption-4" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Fig. 5. </strong> <div class="figure-caption-contents">MG-002 inhibits primary TNBC tumor growth through reduced cell proliferation and increased apoptosis. (<i>A</i>) 4T1-526 mammary tumors were allowed to develop in the mammary fat pads of BALB/c mice and upon reaching ~100 mm<sup>3</sup>, the animals were randomized into three groups, which were treated by PO every 3 d with MG-002 (0.5 mg/kg), eFT226 (0.5 mg/kg) or vehicle control (n = 12 tumors/group). The data is shown as average tumor volume ± SEM. At the experimental endpoint, animals (n = 6 mice per group) were assessed for the (<i>B</i>) average change in mouse weight or (<i>C</i>) their liver weights. (<i>D</i>–<i>F</i>) IHC analysis of 4T1-526 tumors treated with 0.5 mg/kg MG-002 or vehicle control using (<i>D</i>) Ki67, (<i>E</i>) cleaved Caspase-3, and (<i>F</i>) Myc-specific antibodies. The data are shown as % positive cells ± SD and are representative of 9 to 10 tumors per group. (<i>G</i>) Representative IHC images for the graphs depicted in panel <i>D</i>–<i>F</i>. (scale bar: 100 microns.) (<i>H</i>) Pearson correlation examining the relationship between Myc positivity and either the % Ki67+ or % Cleaved Casp3+ cells (individual vehicle-treated tumors are represented by black dots; individual MG-002 treated tumors are represented by blue dots. For panel <i>A</i>, statistical analysis was performed with a two-way ANOVA (Tukey’s multiple comparisons test). For panels <i>D</i>–<i>F</i>, statistical analysis was performed using a two-tailed (unpaired) Student’s <i>t</i> test. *<i>P</i> < 0.05; **<i>P</i> < 0.01; ***<i>P</i> < 0.001; ****<i>P</i> < 0.0001.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="5" data-label-slug="fig-6"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a776/10823175/73e39cb2b7e4/pnas.2318093121fig06.jpg" itemprop="contentUrl" aria-describedby="figure-caption-5" role="button" data-image-width="4016" data-image-height="1373" data-image-alt="Fig. 6." data-pmc-id="PMC10823175" data-figure-id="fig06"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-5" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a776/10823175/9d471f4bea4a/pnas.2318093121fig06.gif" alt="Fig. 6." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="4016"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="1373"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Fig. 6. </p> </strong> <div class="figure-caption-contents"><p> MG-002 monotherapy prevents the development… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Fig. 6. </p> </strong> <div class="figure-caption-contents"><p> MG-002 monotherapy prevents the development of spontaneous breast cancer lung metastasis. ( <i> A… </i> </p></div> </div> <figcaption id="figure-caption-5" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Fig. 6. </strong> <div class="figure-caption-contents">MG-002 monotherapy prevents the development of spontaneous breast cancer lung metastasis. (<i>A</i>) Diagram outlining the experimental schedule to assess the ability of MG-002 to prevent the formation of spontaneous lung metastases from the primary tumor. (<i>B</i>) Using the experimental protocol outlined in panel <i>A</i>, mice were either treated by PO with MG-002 (0.5 mg/kg) or vehicle control every 3 d until surgical resection. The metastatic area in the lungs was quantified from H&E-stained sections (15 to 16 mice/group) and the average metastatic burden is shown ±SD. (<i>C</i>) Schematic diagram outlining the experimental schedule to assess the ability of MG-002 to treat lung metastases following lung colonization. (<i>D</i>) Using the protocol outlined in panel <i>C</i>, mice were either treated by PO with MG-002 (0.5 mg/kg) or vehicle control every 3 d until the experimental endpoint. The metastatic area in the lungs was quantified from H&E-stained sections (8 to 9 mice/group) and the average metastatic burden is presented ±SD. For panels <i>B</i> and <i>D</i>, representative H&E sections are shown (scale bar, 6 mm.) Statistical analysis was performed using a two-tailed (unpaired) Student’s <i>t</i> test. *<i>P</i> < 0.05.</div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="6" data-label-slug="fig-7"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a776/10823175/e2bf29a23c2b/pnas.2318093121fig07.jpg" itemprop="contentUrl" aria-describedby="figure-caption-6" role="button" data-image-width="4016" data-image-height="2469" data-image-alt="Fig. 7." data-pmc-id="PMC10823175" data-figure-id="fig07"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-6" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a776/10823175/73522bc419c6/pnas.2318093121fig07.gif" alt="Fig. 7." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="4016"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="2469"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Fig. 7. </p> </strong> <div class="figure-caption-contents"><p> MG-002/DXR combination therapy reduces the… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Fig. 7. </p> </strong> <div class="figure-caption-contents"><p> MG-002/DXR combination therapy reduces the growth of established primary TNBC breast tumors and… </p></div> </div> <figcaption id="figure-caption-6" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Fig. 7. </strong> <div class="figure-caption-contents">MG-002/DXR combination therapy reduces the growth of established primary TNBC breast tumors and lung metastases. (<i>A</i>) 4T1-526 mammary tumors were allowed to develop in the mammary fat pads of Balb/c mice and when tumors reached ~100 mm<sup>3</sup>, animals were randomized into four groups: 1) 0.5 mg/kg MG-002 PO; 2) 2.5 mg/kg DXR IP; 3) MG-002/DXR combination treatment using the same concentrations; and 4) vehicle control. Animals were treated every 3 d until the experimental endpoint (n = 10 to 14 tumors/group). The data are shown as average tumor volume ± SEM. (<i>B</i>) At the experimental endpoint, each animal in panel <i>A</i> was measured for the average change in weight from the beginning to the end of the study. (<i>C</i>) Tumors were treated as described in panel <i>A</i>, but mice were sacrificed 4 d after the start of drug treatment. (<i>D</i> and <i>E</i>) Tumors from the mice harvested in panel <i>C</i> were analyzed by immunohistochemistry using (<i>D</i>) Ki67 or (<i>E</i>) cleaved caspase-3 specific antibodies (n = 11 tumors per group). (<i>F</i>) Mice with established metastases (as outlined in Fig. 6<i>C</i>) were randomized into four groups and treated as outlined in panel <i>A</i>. The metastatic area in the lungs was quantified from H&E-stained sections (n = 16 mice/group), and the average metastatic burden is presented ±SD. Statistical analysis was performed with a two-way ANOVA (Tukey’s multiple comparisons test).</div> </figcaption> </figure> </div> <div class="see-all actions-bar"> <button class="show-more" aria-controls="slides-container" data-ga-category="figure" data-ga-action="show_all"> All figures (7) </button> </div>  <div class="pswp figures-dialog" id="figures-dialog" tabindex="-1" role="dialog" aria-hidden="true" data-image-gallery-uid="article-figures" aria-label="Figures Dialog">  <div class="pswp__bg"></div>  <div class="pswp__scroll-wrap">  <div class="pswp__container"> <div class="pswp__item"></div> <div class="pswp__item"></div> <div class="pswp__item"></div> </div>  <div class="pswp__ui pswp__ui--hidden"> <div class="pswp__top-bar">  <div class="pswp__counter"></div> <button class="pswp__button pswp__button--close" title="Close (Esc)"></button> <button class="pswp__button pswp__button--share" title="Share"></button> <button class="pswp__button pswp__button--fs" title="Toggle fullscreen"></button> <button class="pswp__button pswp__button--zoom" title="Zoom in/out"></button>   <div class="pswp__preloader"> <div class="pswp__preloader__icn"> <div class="pswp__preloader__cut"> <div class="pswp__preloader__donut"></div> </div> </div> </div> </div> <div class="pswp__share-modal pswp__share-modal--hidden pswp__single-tap"> <div class="pswp__share-tooltip"></div> </div> <button class="pswp__button pswp__button--arrow--left" title="Previous (arrow left)"> </button> <button class="pswp__button pswp__button--arrow--right" title="Next (arrow right)"> </button> <div class="pswp__caption"> <div class="pswp__caption__center"></div> </div> </div> </div> </div> <div class="figure-dialog-caption"> <div class="figure-caption-link-container"> <a class="figure-caption-link" href="#">See this image and copyright information in PMC</a> </div> <div class="figure-caption-center" data-expand-title="click to show full caption" data-collapse-title="click to hide full caption"> </div> <button class="figure-caption-toggle-btn" aria-label="show full caption" data-expand-text="show full caption" data-collapse-text="hide full caption">  </button> </div> </div> <div class="similar-articles" id="similar"> <h2 class="title"> Similar articles </h2> <ul class="articles-list" id="similar-articles-list"> <li class="full-docsum"> <div class="docsum-content" style="display:inline;"> <a class="docsum-title" href="/29844125/" ref="article_id=29844125&linksrc=similar_articles_link&ordinalpos=1" data-ga-category="similar_article" data-ga-action="29844125" data-ga-label=""> FGFR1-Activated Translation of WNT Pathway Components with Structured 5' UTRs Is Vulnerable to Inhibition of EIF4A-Dependent Translation Initiation. </a> <div class="docsum-citation full-citation"> <span class="docsum-authors full-authors">Nguyen TM, Kabotyanski EB, Dou Y, Reineke LC, Zhang P, Zhang XH, Malovannaya A, Jung SY, Mo Q, Roarty KP, Chen Y, Zhang B, Neilson JR, Lloyd RE, Perou CM, Ellis MJ, Rosen JM.</span> <span class="docsum-authors short-authors">Nguyen TM, et al.</span> <span class="docsum-journal-citation full-journal-citation">Cancer Res. 2018 Aug 1;78(15):4229-4240. doi: 10.1158/0008-5472.CAN-18-0631. 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A second-generation eIF4A RNA helicase inhibitor exploits translational reprogramming as a vulnerability in triple-negative breast cancer - PubMed