BAY-069, a Novel (Trifluoromethyl)pyrimidinedione-Based BCAT1/2 Inhibitor and Chemical Probe
Judith Günther, R.C. Hillig, Katja Zimmermann, Stefan Kaulfuß, Clara Lemos, Duy Nguyen, Hartmut Rehwinkel, Matthew Habgood, Christian Lechner, Roland Neuhaus, Ursula Ganzer, M. W. Drewes, Jijie Chai, Léa Bouché
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.