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

  • J Med Chem. 2023 Feb 20. doi: 10.1021/acs.jmedchem.2c01933.
Fabian Göricke  1 ,  Victoria Vu  2 ,  Leanna Smith  2 ,  Ulrike Scheib  3 ,  Raphael Böhm  3 ,  Namik Akkilic  3 ,  Gerd Wohlfahrt  4 ,  Jörg Weiske  3 ,  Ulf Bömer  3 ,  Krzysztof Brzezinka  3 ,  Niels Lindner  1 ,  Philip Lienau  4 ,  Stefan Gradl  4 ,  Hartmut Beck  1 ,  Peter J Brown  2 ,  Vijayaratnam Santhakumar  2 ,  Masoud Vedadi  2  5 ,  Dalia Barsyte-Lovejoy  2 ,  Cheryl H Arrowsmith  2 ,  Norbert Schmees  3 ,  Kirstin Petersen  4
Affiliations
  • 1. Research & Development, Pharmaceuticals, Bayer AG, 42096 Wuppertal, Germany.
  • 2. Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • 3. Nuvisan Innovation Campus Berlin, 13353 Berlin, Germany.
  • 4. Research & Development, Pharmaceuticals, Bayer AG, 13353 Berlin, Germany.
  • 5. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
PMID: 36802665 DOI: 10.1021/acs.jmedchem.2c01933
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.

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