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 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.