6w2j
From Proteopedia
CPS1 bound to allosteric inhibitor H3B-374
Structural highlights
DiseaseCPSM_HUMAN Defects in CPS1 are the cause of carbamoyl phosphate synthetase 1 deficiency (CPS1D) [MIM:237300. CPS1D is an autosomal recessive disorder of the urea cycle causing hyperammonemia. Clinical features include protein intolerance, intermittent ataxia, seizures, lethargy, developmental delay and mental retardation.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] Note=Genetic variations in CPS1 influence the availability of precursors for nitric oxide (NO) synthesis and play a role in clinical situations where endogenous NO production is critically important, such as neonatal pulmonary hypertension, increased pulmonary artery pressure following surgical repair of congenital heart defects or hepatovenocclusive disease following bone marrow transplantation. Infants with neonatal pulmonary hypertension homozygous for Thr-1406 have lower L-arginine concentrations than neonates homozygous for Asn-1406.[13] FunctionCPSM_HUMAN Involved in the urea cycle of ureotelic animals where the enzyme plays an important role in removing excess ammonia from the cell. Publication Abstract from PubMedCarbamoyl 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 2 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 (25), a potent allosteric inhibitor of CPS1 (IC50 = 66 nM). Discovery of 2,6-Dimethylpiperazines as Allosteric Inhibitors of CPS1.,Rolfe A, Yao S, Nguyen TV, Omoto K, Colombo F, Virrankoski M, Vaillancourt FH, Yu L, Cook A, Reynolds D, Ioannidis S, Zhu P, Larsen NA, Bolduc DM ACS Med Chem Lett. 2020 May 26;11(6):1305-1309. doi:, 10.1021/acsmedchemlett.0c00145. eCollection 2020 Jun 11. PMID:32551016[14] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. Loading citation details.. Citations 1 reviews cite this structure No citations found See AlsoReferences
|
|