2. Academic Validation
  3. Small Molecule Inhibition of CPS1 Activity through an Allosteric Pocket

Small Molecule Inhibition of CPS1 Activity through an Allosteric Pocket

  • Cell Chem Biol. 2020 Mar 19;27(3):259-268.e5. doi: 10.1016/j.chembiol.2020.01.009.
Shihua Yao 1,  Tuong-Vi Nguyen 1,  Alan Rolfe 1,  Anant A Agrawal 1,  Jiyuan Ke 1,  Shouyong Peng 1,  Federico Colombo 1,  Sean Yu 2,  Patricia Bouchard 3,  Jiayi Wu 1,  Kuan-Chun Huang 1,  Xingfeng Bao 1,  Kiyoyuki Omoto 1,  Anand Selvaraj 1,  Lihua Yu 1,  Stephanos Ioannidis 1,  Frédéric H Vaillancourt 1,  Ping Zhu 1,  Nicholas A Larsen 1,  David M Bolduc 4
Affiliations

Affiliations

  • 1 H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA 02139, USA.
  • 2 RMI Laboratories LLC, 418 Industrial Drive, North Wales, PA 19454, USA.
  • 3 NMX Research and Solutions, Inc., 500 Cartier Boulevard W., Laval, Quebec H7V 5B7, Canada.
  • 4 H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA 02139, USA. Electronic address: david_bolduc@h3biomedicine.com.
PMID: 32017919 DOI: 10.1016/j.chembiol.2020.01.009
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.

Keywords

CPS1; carbamoyl phosphate synthetase 1; chemical probe; high-throughput screen; inhibitor; pyrimidine synthesis; urea cycle.

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