{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T22:39:42Z","timestamp":1793399982306,"version":"4.5.0"},"reference-count":28,"publisher":"National Academy of Sciences","issue":"29","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,7,20]]},"abstract":"<jats:p>Activation of the B-cell antigen receptor (BCR) signaling pathway contributes to the initiation and maintenance of B-cell malignancies and autoimmune diseases. The Bruton tyrosine kinase (Btk) is specifically required for BCR signaling as demonstrated by human and mouse mutations that disrupt Btk function and prevent B-cell maturation at steps that require a functional BCR pathway. Herein we describe a selective and irreversible Btk inhibitor, PCI-32765, that is currently under clinical development in patients with B-cell non-Hodgkin lymphoma. We have used this inhibitor to investigate the biologic effects of Btk inhibition on mature B-cell function and the progression of B cell-associated diseases in vivo. PCI-32765 blocked BCR signaling in human peripheral B cells at concentrations that did not affect T cell receptor signaling. In mice with collagen-induced arthritis, orally administered PCI-32765 reduced the level of circulating autoantibodies and completely suppressed disease. PCI-32765 also inhibited autoantibody production and the development of kidney disease in the MRL-Fas(lpr) lupus model. Occupancy of the Btk active site by PCI-32765 was monitored in vitro and in vivo using a fluorescent affinity probe for Btk. Active site occupancy of Btk was tightly correlated with the blockade of BCR signaling and in vivo efficacy. Finally, PCI-32765 induced objective clinical responses in dogs with spontaneous B-cell non-Hodgkin lymphoma. These findings support Btk inhibition as a therapeutic approach for the treatment of human diseases associated with activation of the BCR pathway.<\/jats:p>","DOI":"10.1073\/pnas.1004594107","type":"journal-article","created":{"date-parts":[[2010,7,6]],"date-time":"2010-07-06T22:23:58Z","timestamp":1278455038000},"page":"13075-13080","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1436,"title":["The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy"],"prefix":"10.1073","volume":"107","author":[{"given":"Lee A.","family":"Honigberg","sequence":"first","affiliation":[{"name":"Pharmacyclics, Sunnyvale, CA 94085-4521;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley M.","family":"Smith","sequence":"additional","affiliation":[{"name":"Pharmacyclics, Sunnyvale, CA 94085-4521;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mint","family":"Sirisawad","sequence":"additional","affiliation":[{"name":"Pharmacyclics, Sunnyvale, CA 94085-4521;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Verner","sequence":"additional","affiliation":[{"name":"Pharmacyclics, Sunnyvale, CA 94085-4521;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Loury","sequence":"additional","affiliation":[{"name":"Pharmacyclics, Sunnyvale, CA 94085-4521;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betty","family":"Chang","sequence":"additional","affiliation":[{"name":"Pharmacyclics, Sunnyvale, CA 94085-4521;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shyr","family":"Li","sequence":"additional","affiliation":[{"name":"Celera Genomics, South San Francisco, CA 94080;"},{"name":"Exelixis, South San Francisco, CA 94080;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengying","family":"Pan","sequence":"additional","affiliation":[{"name":"Celera Genomics, South San Francisco, CA 94080;"},{"name":"Peking University Shenzhen Graduate School, Shenzhen City 518055, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas H.","family":"Thamm","sequence":"additional","affiliation":[{"name":"Colorado State University Animal Cancer Center, Fort Collins, CO 80523; 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