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Biochemistry. 2018 Jul 3;57(26):3564-3575. doi: 10.1021/acs.biochem.8b00391. Epub 2018 Jun 14.

Targeting the C481S Ibrutinib-Resistance Mutation in Bruton's Tyrosine Kinase Using PROTAC-Mediated Degradation.

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Department of Molecular, Cellular, and Developmental Biology , Yale University , New Haven , Connecticut 06511 , United States.
Division of Pharmaceutics & Pharmaceutical Chemistry, College of Pharmacy , The Ohio State University , Columbus , Ohio 43210 , United States.
Department of Internal Medicine, Division of Hematology , The Ohio State University , Columbus , Ohio 43210 , United States.
Center for Biostatistics , The Ohio State University , Columbus , Ohio 43210 , United States.
Department of Chemistry , Yale University , New Haven , Connecticut 06520-8107 , United States.
Department of Pharmacology , Yale University , New Haven , Connecticut 06520-8066 , United States.


Inhibition of Bruton's tyrosine kinase (BTK) with the irreversible inhibitor ibrutinib has emerged as a transformative treatment option for patients with chronic lymphocytic leukemia (CLL) and other B-cell malignancies, yet >80% of CLL patients develop resistance due to a cysteine to serine mutation at the site covalently bound by ibrutinib (C481S). Currently, an effective treatment option for C481S patients exhibiting relapse to ibrutinib does not exist, and these patients have poor outcomes. To address this, we have developed a PROteolysis TArgeting Chimera (PROTAC) that induces degradation of both wild-type and C481S mutant BTK. We selected a lead PROTAC, MT-802, from several candidates on the basis of its potency to induce BTK knockdown. MT-802 recruits BTK to the cereblon E3 ubiquitin ligase complex to trigger BTK ubiquitination and degradation via the proteasome. MT-802 binds fewer off-target kinases than ibrutinib does and retains an equivalent potency (>99% degradation at nanomolar concentrations) against wild-type and C481S BTK. In cells isolated from CLL patients with the C481S mutation, MT-802 is able to reduce the pool of active, phosphorylated BTK whereas ibrutinib cannot. Collectively, these data provide a basis for further preclinical study of BTK PROTACs as a novel strategy for treatment of C481S mutant CLL.

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