{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T16:32:24Z","timestamp":1791995544426,"version":"4.4.0"},"reference-count":0,"publisher":"American Society of Hematology","license":[{"start":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T00:00:00Z","timestamp":1676505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:p>Bruton tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a major therapeutic target for B-cell driven malignancies. However, approved covalent BTK inhibitors (cBTKi) are associated with treatment limitations due to off-target side effects, suboptimal oral pharmacology, and development of resistance mutations (eg, C481) that prevent inhibitor binding. Here we describe the preclinical profile of pirtobrutinib, a potent, highly selective, non-covalent (reversible) BTK inhibitor. Pirtobrutinib binds BTK with an extensive network of interactions to BTK and water molecules in the adenosine triphosphate (ATP)-binding region and shows no direct interaction with C481. As a result, pirtobrutinib inhibits both BTK and BTK C481 substitution mutants in enzymatic and cell-based assays with similar potencies. In differential scanning fluorimetry studies, BTK bound to pirtobrutinib exhibited a higher melting temperature than cBTKi-bound BTK. Pirtobrutinib, but not cBTKi, prevented Y551 phosphorylation in the activation loop. These data suggest pirtobrutinib uniquely stabilizes BTK in a closed, inactive conformation. Pirtobrutinib inhibits BTK signaling and cell proliferation in multiple B-cell lymphoma cell lines and significantly inhibits tumor growth in human lymphoma xenografts in vivo. Enzymatic profiling showed pirtobrutinib was highly selective for BTK in &amp;gt;98% of the human kinome, and in follow-up cellular studies pirtobrutinib retained &amp;gt;100-fold selectivity over other tested kinases. Collectively, these findings suggest pirtobrutinib represents a novel BTK inhibitor with improved selectivity and unique pharmacologic, biophysical and structural attributes with the potential to treat B-cell driven cancers with improved precision and tolerability. Pirtobrutinib is being tested in phase 3 clinical studies for a variety of B-cell malignancies.<\/jats:p>","DOI":"10.1182\/blood.2022018674","type":"journal-article","created":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T16:17:02Z","timestamp":1676564222000},"update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":73,"title":["Pirtobrutinib preclinical characterization: a highly selective, non-covalent (reversible) BTK inhibitor"],"prefix":"10.1182","author":[{"given":"Eliana B","family":"Gomez","sequence":"first","affiliation":[{"name":"Loxo Oncology, Inc., Stamford, Connecticut, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Ebata","sequence":"additional","affiliation":[{"name":"Loxo@Lilly, SOUTH SAN FRANCISCO, California, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hetal S","family":"Randeria","sequence":"additional","affiliation":[{"name":"Loxo@Lilly, South San Francisco, California, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary S","family":"Rosendahl","sequence":"additional","affiliation":[{"name":"Loxo@Lilly, Louisville, Colorado, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernst Peder","family":"Cedervall","sequence":"additional","affiliation":[{"name":"Loxo@Lilly, Louisville, Colorado, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tony H","family":"Morales","sequence":"additional","affiliation":[{"name":"Loxo@Lilly, Louisville, Colorado, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren M","family":"Hanson","sequence":"additional","affiliation":[{"name":"Loxo@Lilly, Louisville, Colorado, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas E","family":"Brown","sequence":"additional","affiliation":[{"name":"Loxo@Lilly, Indianapolis, Indiana, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueqian","family":"Gong","sequence":"additional","affiliation":[{"name":"Loxo@Lilly, Indianapolis, Indiana, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer Rachelle","family":"Stephens","sequence":"additional","affiliation":[{"name":"Loxo@Lilly, Indianapolis, Indiana, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Loxo@Lilly, Indianapolis, Indiana, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Lippincott","sequence":"additional","affiliation":[{"name":"Loxo@Lilly, Louisville, Colorado, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin S.","family":"Ku","sequence":"additional","affiliation":[{"name":"Loxo@Lilly, South San Francisco, California, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A","family":"Walgren","sequence":"additional","affiliation":[{"name":"Loxo@Lilly, Indianapolis, Indiana, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo B","family":"Abada","sequence":"additional","affiliation":[{"name":"Loxo@Lilly, Indianapolis, Indiana, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua A","family":"Ballard","sequence":"additional","affiliation":[{"name":"Loxo@Lilly, Louisville, Colorado, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles K","family":"Allerston","sequence":"additional","affiliation":[{"name":"Loxo@Lilly, Louisville, Colorado, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara J","family":"Brandhuber","sequence":"additional","affiliation":[{"name":"Loxo@Lilly, Louisville, Colorado, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2023,2,16]]},"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/doi\/10.1182\/blood.2022018674\/2034256\/blood.2022018674.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/doi\/10.1182\/blood.2022018674\/2034256\/blood.2022018674.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T16:17:04Z","timestamp":1676564224000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/doi\/10.1182\/blood.2022018674\/494500\/Pirtobrutinib-preclinical-characterization-a"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,16]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1182\/blood.2022018674","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,16]]},"article-number":"blood.2022018674"}}