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
  • 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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