6W2J

CPS1 bound to allosteric inhibitor H3B-374

Summary for 6W2J

• Entry DOI: 10.2210/pdb6w2j/pdb
• Descriptor: Carbamoyl-phosphate synthase [ammonia], mitochondrial, (2-fluoranyl-4-methoxy-phenyl)-[(3~{R},5~{R})-4-(2-fluoranyl-4-methoxy-phenyl)carbonyl-3,5-dimethyl-piperazin-1-yl]methanone, ZINC ION, ... (5 entities in total)
• Functional Keywords: inhibitor, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 331286.82

Authors

Larsen, N.A.,Nguyen, T.V. (deposition date: 2020-03-05, release date: 2021-01-13, Last modification date: 2023-10-18)

Primary citation

Rolfe, A.,Yao, S.,Nguyen, T.V.,Omoto, K.,Colombo, F.,Virrankoski, M.,Vaillancourt, F.H.,Yu, L.,Cook, A.,Reynolds, D.,Ioannidis, S.,Zhu, P.,Larsen, N.A.,Bolduc, D.M.
Discovery of 2,6-Dimethylpiperazines as Allosteric Inhibitors of CPS1.
Acs Med.Chem.Lett., 11:1305-1309, 2020

PubMed Abstract: Carbamoyl phosphate synthetase 1 (CPS1) is a potential synthetic lethal target in LKB1-deficient nonsmall cell lung cancer, where its overexpression supports the production of pyrimidine synthesis. In other cancer types, CPS1 overexpression and activity may prevent the accumulation of toxic levels of intratumoral ammonia to support tumor growth. Herein we report the discovery of a novel series of potent and selective small-molecule inhibitors of CPS1. Piperazine was initially identified as a promising CPS1 inhibitor through a high-throughput screening effort. Subsequent structure-activity relationship optimization and structure-based drug design led to the discovery of piperazine H3B-616 (), a potent allosteric inhibitor of CPS1 (IC = 66 nM).

PubMed: 32551016
DOI: 10.1021/acsmedchemlett.0c00145

Experimental method

X-RAY DIFFRACTION (2.62 Å)