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.

中文翻译：

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通过变构口袋抑制 CPS1 活性的小分子。

氨基甲酰磷酸合成酶 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基甲酰磷酸。在癌症中，CPS1 过表达支持嘧啶合成以促进某些癌症类型的肿瘤生长，而在其他类型中，CPS1 活性可防止肿瘤内有毒水平氨的积聚，从而使肿瘤持续生长。因此，靶向 CPS1 抑制剂可能为肿瘤过度表达 CPS1 的癌症患者提供治疗益处。在本文中，我们描述了小分子 CPS1 抑制剂的发现，该抑制剂与以前未知的变构口袋结合，在氨基甲酰磷酸合成的第一步中阻止 ATP 水解。CPS1 抑制剂在细胞检测中具有活性，阻断尿素合成和 CPS1 对嘧啶生物合成途径的支持，同时对 CPS2 没有活性。这些新发现的 CPS1 抑制剂是为研究人员提供探索 CPS1 癌症生物学的宝贵工具的第一步。