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

Fabian GörickeVictoria VuLeanna SmithUlrike ScheibRaphael BöhmNamik AkkilicGerd WohlfahrtJörg WeiskeUlf BömerKrzysztof BrzezinkaNiels LindnerPhilip LienauStefan GradlHartmut BeckPeter J BrownVijayaratnam SanthakumarMasoud VedadiDalia Barsyte-LovejoyCheryl H ArrowsmithNorbert SchmeesKirstin Petersen
Published in: Journal of medicinal chemistry (2023)
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.
Keyphrases
  • small molecule
  • high throughput
  • stem cells
  • single cell
  • oxidative stress
  • anti inflammatory
  • cell proliferation
  • cell therapy
  • transcription factor
  • living cells
  • pi k akt
  • capillary electrophoresis