1区 · 医学
Article
作者: Santhakumar, Vijayaratnam ; Brzezinka, Krzysztof ; Göricke, Fabian ; Scheib, Ulrike ; Vedadi, Masoud ; Brown, Peter J. ; Smith, Leanna ; Vu, Victoria ; Arrowsmith, Cheryl H. ; Beck, Hartmut ; Schmees, Norbert ; Akkilic, Namik ; Weiske, Jörg ; Petersen, Kirstin ; Böhm, Raphael ; Gradl, Stefan ; Lienau, Philip ; Barsyte-Lovejoy, Dalia ; Lindner, Niels ; Bömer, Ulf ; Wohlfahrt, Gerd
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.
