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• W3196331199 abstract "Bruton's tyrosine kinase (BTK) is a key drug target for B-cell related malignancies. Irreversible covalent BTK inhibitors have been approved for the treatment of B-cell malignancies, yet BTK C481S mutation at the covalent binding site has caused drug-resistance of BTK covalent binding inhibitors. The proteolysis targeting chimera (PROTAC) technology increases the sensitivity to drug-resistant targets compared to classic inhibitors, which provides a new strategy for mutant BTK related B-cell malignancies. ARQ531, a reversible non-covalent BTK inhibitor that inhibits wild type (WT) and mutated BTK with high selectivity, could be an ideal warhead for PROTACs targeting the mutant BTK. Herein, we designed a novel series of PROTACs using the selective non-covalent BTK inhibitor ARQ531 as warhead, with the goal of improving the degradation of both wild-type and C481S mutant BTKs, and increasing the selectivity of BTK over other kinases. This effort will provide some basis for further preclinical study of BTK PROTACs as a novel strategy for treatment of B-cell lymphomas." @default.
• W3196331199 created "2021-09-13" @default.
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• W3196331199 date "2021-12-01" @default.
• W3196331199 modified "2023-10-06" @default.
• W3196331199 title "Discovery of novel BTK PROTACs for B-Cell lymphomas" @default.
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• W3196331199 doi "https://doi.org/10.1016/j.ejmech.2021.113820" @default.
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