Carbamoyl phosphate synthetase 1 (CPS1) is a potential synthetic lethal target in LKB1-deficient nonsmall cell lung cancer, where its overexpression supports the production of pyrimidine synthesis. In other cancer types, CPS1 overexpression and activity may prevent the accumulation of toxic levels of intratumoral ammonia to support tumor growth. Herein we report the discovery of a novel series of potent and selective small-molecule inhibitors of CPS1. Piperazine 2 was initially identified as a promising CPS1 inhibitor through a high-throughput screening effort. Subsequent structure–activity relationship optimization and structure-based drug design led to the discovery of piperazine H3B-616 (25), a potent allosteric inhibitor of CPS1 (IC₅₀ = 66 nM).

中文翻译：

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发现2,6-二甲基哌嗪作为CPS1的变构抑制剂。

氨基甲酰磷酸合成酶1（CPS1）是LKB1缺陷型非小细胞肺癌的潜在合成致死靶标，其过表达支持嘧啶合成的产生。在其他类型的癌症中，CPS1的过度表达和活性可能阻止肿瘤内氨水的毒性水平的积累，以支持肿瘤的生长。在这里，我们报告发现了一系列新型的有效和选择性的CPS1小分子抑制剂。通过高通量筛选工作，哌嗪2最初被鉴定为有前途的CPS1抑制剂。随后的结构-活性关系优化和基于结构的药物设计导致发现哌嗪H3B-616（25），这是一种有效的CPS1变构抑制剂（IC ₅₀ = 66 nM）。