{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:32:34Z","timestamp":1785407554549,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,6]]},"group-title":"Biochemistry","reference-count":48,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["1R21CA280163-01"],"award-info":[{"award-number":["1R21CA280163-01"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/053gv2m95","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>The cysteine to serine mutation at residue 481 of Bruton\u2019s tyrosine kinase (BTK) is the most common mechanism of clinical resistance against ibrutinib for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia. We report small molecule ligands containing chiral \u03b2-lactone electrophiles to address this challenge. The asymmetric warhead enabled stereoselective covalent modification of wild-type and ibrutinib-resistant mutant BTK(C481S) through distinct sites of reactivity. Building on these findings, we developed kinase-directed \u03b2-lactone probes and demonstrated that individual enantiomers preferentially engage distinct subsets of the kinome. These studies establish \u03b2-lactones as stereochemically encodable covalent warheads whose stereochemistry can serve as a selectivity filter in covalent drug discovery.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Abstract Figure<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" fig-type=\"figure\" orientation=\"portrait\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"736436v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.03.736436","type":"posted-content","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T13:05:19Z","timestamp":1783343119000},"source":"Crossref","is-referenced-by-count":0,"title":["Stereoselective Covalent Targeting of BTK(C481S) and Kinases with \u03b2-Lactone Electrophiles"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8190-1043","authenticated-orcid":false,"given":"Celine D.","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Chemistry, University of California, Berkeley, California 94720, USA"},{"name":"Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, California 94720, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Polina E.","family":"Barzova","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of California, Berkeley, California 94720, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Robles","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of California, Berkeley, California 94720, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethan S.","family":"Toriki","sequence":"additional","affiliation":[{"name":"Novartis-Berkeley 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