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发现并表征 BAY-805，一种强效和选择性的泛素特异性蛋白酶 USP21 的抑制剂。

Discovery and Characterization of BAY-805, a Potent and Selective Inhibitor of Ubiquitin-Specific Protease USP21.

机构信息

Research & Development, Pharmaceuticals, Bayer AG, 42096 Wuppertal, Germany.

Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.

出版信息

J Med Chem. 2023 Mar 9;66(5):3431-3447. doi: 10.1021/acs.jmedchem.2c01933. Epub 2023 Feb 20.

DOI:10.1021/acs.jmedchem.2c01933
PMID:36802665
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10009755/
Abstract

USP21 belongs to the ubiquitin-specific protease (USP) subfamily of deubiquitinating enzymes (DUBs). Due to its relevance in tumor development and growth, USP21 has been reported as a promising novel therapeutic target for cancer treatment. Herein, we present the discovery of the first highly potent and selective USP21 inhibitor. Following high-throughput screening and subsequent structure-based optimization, we identified BAY-805 to be a non-covalent inhibitor with low nanomolar affinity for USP21 and high selectivity over other DUB targets as well as kinases, proteases, and other common off-targets. Furthermore, surface plasmon resonance (SPR) and cellular thermal shift assays (CETSA) demonstrated high-affinity target engagement of BAY-805, resulting in strong NF-κB activation in a cell-based reporter assay. To the best of our knowledge, BAY-805 is the first potent and selective USP21 inhibitor and represents a valuable high-quality in vitro chemical probe to further explore the complex biology of USP21.

摘要

USP21 属于泛素特异性蛋白酶（USP）去泛素化酶（DUB）亚家族。由于其在肿瘤发生和生长中的相关性，USP21 已被报道为癌症治疗的一种有前途的新型治疗靶点。在此，我们介绍了第一个高效且选择性的 USP21 抑制剂的发现。经过高通量筛选和随后的基于结构的优化，我们确定 BAY-805 是一种非共价抑制剂，对 USP21 的亲和力低至纳摩尔级，对其他 DUB 靶点以及激酶、蛋白酶和其他常见的非靶点具有高选择性。此外，表面等离子体共振（SPR）和细胞热转移分析（CETSA）证明了 BAY-805 与靶标的高亲和力结合，导致基于细胞的报告基因测定中 NF-κB 的强烈激活。据我们所知，BAY-805 是第一个高效且选择性的 USP21 抑制剂，是进一步探索 USP21 复杂生物学的有价值的高质量体外化学探针。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/492c/10009755/d457906769a6/jm2c01933_0015.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/492c/10009755/ff6906595a13/jm2c01933_0002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/492c/10009755/66bceaa620a0/jm2c01933_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/492c/10009755/9b404ba41b26/jm2c01933_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/492c/10009755/9b1b3c1aff93/jm2c01933_0007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/492c/10009755/5190ffe91f8c/jm2c01933_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/492c/10009755/25ea2227881a/jm2c01933_0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/492c/10009755/94dd2e822c9f/jm2c01933_0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/492c/10009755/f2572a320d95/jm2c01933_0012.jpg
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