Open AccessDiscovery of 2,6-Dimethylpiperazines as Allosteric Inhibitors of CPS1
Author(s) -
Alan Rolfe,
Shihua Yao,
Toung-Vi Nguyen,
Kiyoyuki Omoto,
Federico Colombo,
Milena Virrankoski,
Frédéric H. Vaillancourt,
Lihua Yu,
Andrew S. Cook,
Dominic J. Reynolds,
Stephanos Ioannidis,
Ping Zhu,
Nicholas Larsen,
David M. Bolduc
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00145
Subject(s) - allosteric regulation , piperazine , drug discovery , chemistry , pharmacology , ic50 , cancer research , enzyme , biochemistry , biology , in vitro
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 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 (IC 50 = 66 nM).