H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA 02139, USA.
RMI Laboratories LLC, 418 Industrial Drive, North Wales, PA 19454, USA.
Cell Chem Biol. 2020 Mar 19;27(3):259-268.e5. doi: 10.1016/j.chembiol.2020.01.009. Epub 2020 Feb 3.
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.
氨甲酰磷酸合成酶 1（CPS1）催化氨解毒尿素循环的第一步，在生理条件下将氨转化为氨甲酰磷酸。在癌症中，CPS1 的过表达支持嘧啶合成，从而促进某些癌症类型的肿瘤生长，而在其他癌症类型中，CPS1 活性可防止肿瘤内氨的毒性积聚，从而允许肿瘤持续生长。因此，针对 CPS1 的抑制剂可能为 CPS1 过表达的癌症患者提供治疗益处。本文描述了小分子 CPS1 抑制剂的发现，这些抑制剂结合到以前未知的变构口袋中，以阻断氨甲酰磷酸合成第一步中的 ATP 水解。CPS1 抑制剂在细胞测定中具有活性，可阻断尿素合成和 CPS1 对嘧啶生物合成途径的支持，而对 CPS2 没有活性。这些新发现的 CPS1 抑制剂为研究人员提供有价值的工具，以探索 CPS1 癌症生物学迈出了第一步。
