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Carver Charitable Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Experimental Cancer Medicine Centre","award":["C10604\/A25151"],"award-info":[{"award-number":["C10604\/A25151"]}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Inhibition of Bruton\u2019s tyrosine kinase (BTK) has proven to be highly effective in the treatment of B-cell malignancies such as chronic lymphocytic leukemia (CLL), autoimmune disorders, and multiple sclerosis. Since the approval of the first BTK inhibitor (BTKi), Ibrutinib, several other inhibitors including Acalabrutinib, Zanubrutinib, Tirabrutinib, and Pirtobrutinib have been clinically approved. All are covalent active site inhibitors, with the exception of the reversible active site inhibitor Pirtobrutinib. The large number of available inhibitors for the BTK target creates challenges in choosing the most appropriate BTKi for treatment. Side-by-side comparisons in CLL have shown that different inhibitors may differ in their treatment efficacy. Moreover, the nature of the resistance mutations that arise in patients appears to depend on the specific BTKi administered. We have previously shown that Ibrutinib binding to the kinase active site causes unanticipated long-range effects on the global conformation of BTK (Joseph et al., 2020). Here, we show that binding of each of the five approved BTKi to the kinase active site brings about distinct allosteric changes that alter the conformational equilibrium of full-length BTK. Additionally, we provide an explanation for the resistance mutation bias observed in CLL patients treated with different BTKi and characterize the mechanism of action of two common resistance mutations: BTK T474I and L528W.<\/jats:p>","DOI":"10.7554\/elife.95488","type":"journal-article","created":{"date-parts":[[2024,3,23]],"date-time":"2024-03-23T09:25:24Z","timestamp":1711185924000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.95488","source":"Crossref","is-referenced-by-count":8,"title":["Impact of the clinically approved BTK inhibitors on the conformation of full-length BTK and analysis of the development of BTK resistance mutations in chronic lymphocytic leukemia"],"prefix":"10.7554","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7122-8553","authenticated-orcid":true,"given":"Raji E","family":"Joseph","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04rswrd78","id-type":"ROR","asserted-by":"publisher"}],"name":"Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University","place":["Ames, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"corresponding-author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6133-5689","authenticated-orcid":true,"given":"Thomas E","family":"Wales","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04t5xt781","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemistry and Chemical Biology, Northeastern University","place":["Boston, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1870-9782","authenticated-orcid":true,"given":"Sandrine","family":"Jayne","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04h699437","id-type":"ROR","asserted-by":"publisher"}],"name":"The Ernest and Helen Scott Haematological Research Institute, Leicester Cancer Research Centre, College of Life Sciences, University of Leicester","place":["Leicester, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Robert G","family":"Britton","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04h699437","id-type":"ROR","asserted-by":"publisher"}],"name":"The Ernest and Helen Scott Haematological Research Institute, Leicester Cancer Research Centre, College of Life Sciences, University of Leicester","place":["Leicester, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"D Bruce","family":"Fulton","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04rswrd78","id-type":"ROR","asserted-by":"publisher"}],"name":"Roy J. 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