Small Molecule Inhibition of CPS1 Activity through an Allosteric Pocket.

Cell Chemical Biology
Shihua YaoDavid M Bolduc

Abstract

Carbamoyl phosphate synthetase 1 (CPS1) catalyzes the first step in the ammonia-detoxifying urea cycle, converting ammonia to carbamoyl phosphate under physiologic conditions. In cancer, CPS1 overexpression supports pyrimidine synthesis to promote tumor growth in some cancer types, while in others CPS1 activity prevents the buildup of toxic levels of intratumoral ammonia to allow for sustained tumor growth. Targeted CPS1 inhibitors may, therefore, provide a therapeutic benefit for cancer patients with tumors overexpressing CPS1. Herein, we describe the discovery of small-molecule CPS1 inhibitors that bind to a previously unknown allosteric pocket to block ATP hydrolysis in the first step of carbamoyl phosphate synthesis. CPS1 inhibitors are active in cellular assays, blocking both urea synthesis and CPS1 support of the pyrimidine biosynthetic pathway, while having no activity against CPS2. These newly discovered CPS1 inhibitors are a first step toward providing researchers with valuable tools for probing CPS1 cancer biology.

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Citations

Feb 9, 2021·Frontiers in Physiology·Nantaporn HaskinsLjubica Caldovic
Mar 24, 2020·Cell Chemical Biology·Ayumu TaguchiSamir M Hanash
Dec 16, 2020·Molecular Genetics and Metabolism·Matthew Nitzahn, Gerald S Lipshutz
Jun 20, 2020·ACS Medicinal Chemistry Letters·Alan RolfeDavid M Bolduc
Sep 2, 2021·Molecular Cell·Emma HajajAyelet Erez

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