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BAY-069, a Novel (Trifluoromethyl)pyrimidinedione-Based BCAT1/2 Inhibitor and Chemical Probe
Judith Günther1, Roman C Hillig1, Katja Zimmermann2
1Research & Development, Pharmaceuticals, Bayer Pharma AG, Müllerstrasse 178, 13353Berlin, Germany.
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.
Insights
Researchers discovered novel (trifluoromethyl)pyrimidinediones as potent inhibitors of branched-chain amino acid transaminases (BCAT1/2). The dual inhibitor BAY-069 shows high cellular activity, offering a new tool for cancer research.
Area of Science:
- Biochemistry
- Enzymology
- Cancer Biology
Background:
- Branched-chain amino acid transaminases (BCATs) are crucial enzymes in branched-chain amino acid catabolism.
- BCATs play a significant role in the progression of various cancer types.
Purpose of the Study:
- To identify and develop novel inhibitors targeting BCAT1 and BCAT2.
- To characterize the structural and functional properties of new BCAT1/2 inhibitors.
Main Methods:
- High-throughput screening (HTS) to identify initial hits.
- Structure-guided drug design and optimization using X-ray crystallography.
- Cellular assays to evaluate inhibitor activity and selectivity.
Main Results:
- Discovery of a new structural class of BCAT1/2 inhibitors: (trifluoromethyl)pyrimidinediones.
- Identification of a potent dual BCAT1/2 inhibitor, BAY-069, with high cellular activity and selectivity.
- BAY-069 and a control (BAY-771) were provided as chemical probes to the Structural Genomics Consortium.
Conclusions:
- The novel (trifluoromethyl)pyrimidinediones represent a promising class of BCAT1/2 inhibitors.
- BAY-069 serves as a valuable chemical probe for further research into BCAT function in cancer.
- These findings open new avenues for therapeutic strategies targeting BCATs in oncology.
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