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

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 cla...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2022-11, Vol.65 (21), p.14366-14390
Main Authors: Günther, Judith, Hillig, Roman C., Zimmermann, Katja, Kaulfuss, Stefan, Lemos, Clara, Nguyen, Duy, Rehwinkel, Hartmut, Habgood, Matthew, Lechner, Christian, Neuhaus, Roland, Ganzer, Ursula, Drewes, Mark, Chai, Jijie, Bouché, Léa
Format: Article
Language:English
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.2c00441