2. Academic Validation
  3. BAY-069, a Novel (Trifluoromethyl)pyrimidinedione-Based BCAT1/2 Inhibitor and Chemical Probe

BAY-069, a Novel (Trifluoromethyl)pyrimidinedione-Based BCAT1/2 Inhibitor and Chemical Probe

  • J Med Chem. 2022 Nov 10;65(21):14366-14390. doi: 10.1021/acs.jmedchem.2c00441.
Judith Günther 1,  Roman C Hillig 1,  Katja Zimmermann 2,  Stefan Kaulfuss 1,  Clara Lemos 1,  Duy Nguyen 1,  Hartmut Rehwinkel 1,  Matthew Habgood 3,  Christian Lechner 1,  Roland Neuhaus 1,  Ursula Ganzer 1,  Mark Drewes 4,  Jijie Chai 5,  Léa Bouché 1
Affiliations

Affiliations

  • 1 Research & Development, Pharmaceuticals, Bayer Pharma AG, Müllerstrasse 178, 13353Berlin, Germany.
  • 2 Research & Development, Pharmaceuticals, Bayer Pharma AG, Aprather Weg 18a, 42113Wuppertal, Germany.
  • 3 Evotec (UK) Ltd., 114 Innovation Drive, Milton Park, Abingdon, OxfordshireOX14 4RZ, U.K.
  • 4 Research & Development BCS, Bayer AG, Alfred-Nobel-Strasse 50, 40789Monheim, Germany.
  • 5 School of Life Sciences, Tsinghua University, 100084Beijing, China.
PMID: 36261130 DOI: 10.1021/acs.jmedchem.2c00441
Abstract

The branched-chain amino acid transaminases (BCATs) are enzymes that catalyze the first reaction of catabolism of the essential branched-chain Amino acids to branched-chain keto acids to form glutamate. They are known to play a key role in different Cancer types. Here, we report a new structural class of BCAT1/2 inhibitors, (trifluoromethyl)pyrimidinediones, identified by a high-throughput screening campaign and subsequent optimization guided by a series of X-ray crystal structures. Our potent dual BCAT1/2 inhibitor BAY-069 displays high cellular activity and very good selectivity. Along with a negative control (BAY-771), BAY-069 was donated as a chemical probe to the Structural Genomics Consortium.

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