期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 225, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.113820
关键词
BTK; PROTACs; B-Cell Lymphomas; ARQ531; Protein degradation
资金
- Natural National Science Foundation of China [81874287, 81973163, 82003577]
- Shanghai Bio-pharmaceutical Science and Technology Supporting Plan [19431900100]
- National Science and Technology Major Project [2018ZX09711002-003-014]
- Natural Science Foundation of Shanghai [19ZR1436700]
BTK is a key drug target for B-cell malignancies, and the covalent BTK inhibitors face drug resistance issues. PROTAC technology can increase sensitivity to drug-resistant targets, and ARQ531 as a non-covalent BTK inhibitor may serve as an ideal warhead for PROTACs.
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. (C) 2021 Elsevier Masson SAS. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据