Small Molecule Inhibition of CPS1 Activity through an Allosteric Pocket

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.

 

Comments：

CPS1 plays an important role in the urea cycle and its overexpression in cancer cells can promote tumor growth, making it an attractive target for therapeutic intervention. The discovery of small-molecule CPS1 inhibitors that block ATP hydrolysis and are active in cellular assays is a promising development. The fact that these inhibitors do not affect CPS2 activity is also interesting, as it suggests a degree of selectivity that could be important for minimizing potential off-target effects.

Overall, these newly discovered CPS1 inhibitors could provide valuable tools for researchers studying the role of CPS1 in cancer biology, as well as serving as potential leads for the development of new cancer therapies. It will be interesting to see how this research progresses and whether these inhibitors ultimately prove to be effective in preclinical and clinical studies.

Related Products

Cat.No.	Product Name	Information
S3244	H3B-120	H3B-120 is a competitive, selective and allosteric inhibitor of carbamoyl phosphate synthetase 1 (CPS1) with IC50 of 1.5 μM and Ki of 1.4 μM. H3B-120 exhibits anti-tumor activity.

Related Targets

CPSase