7NY2

CRYSTAL STRUCTURE OF HUMAN CYTOSOLIC BRANCHED-CHAIN AMINOTRANSFERASE (BCAT1) IN COMPLEX WITH PLP AND SMALL MOLECULE INHIBITOR COMPOUND 35

Summary for 7NY2

• Entry DOI: 10.2210/pdb7ny2/pdb
• Related: 7NTR 7NWA 7NWB 7NWC 7NWE 7NWM 7NXN 7NXO
• Descriptor: Branched-chain-amino-acid aminotransferase, cytosolic, 4-[2,4-bis(oxidanylidene)-6-(trifluoromethyl)-1H-pyrimidin-3-yl]-2-(2-methylphenoxy)naphthalene-1-carbonitrile, PYRIDOXAL-5'-PHOSPHATE, ... (5 entities in total)
• Functional Keywords: branched-chain-amino-acid aminotransferase, pyridoxal-phosphate-dependent aminotransferase, transferase, small molecule inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 87973.95

Authors

Hillig, R.C. (deposition date: 2021-03-19, release date: 2022-11-02, Last modification date: 2024-01-31)

Primary citation

Gunther, J.,Hillig, R.C.,Zimmermann, K.,Kaulfuss, S.,Lemos, C.,Nguyen, D.,Rehwinkel, H.,Habgood, M.,Lechner, C.,Neuhaus, R.,Ganzer, U.,Drewes, M.,Chai, J.,Bouche, L.
BAY-069, a Novel (Trifluoromethyl)pyrimidinedione-Based BCAT1/2 Inhibitor and Chemical Probe.
J.Med.Chem., 65:14366-14390, 2022

PubMed 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.

PubMed: 36261130
DOI: 10.1021/acs.jmedchem.2c00441

Experimental method

X-RAY DIFFRACTION (2.31 Å)