Zhang Junjie, Liu Benjin, Ren Ruyue, Song Shanshan, Bao Xubin, Huan Xiajuan, Li Hongrui, Xu Jiahao, Yu Ting, Wang Ruifeng, Miao Ze-Hong, Xiong Bing, He Jinxue, Liu Tongchao
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China.
State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
J Med Chem. 2025 Feb 13;68(3):3673-3699. doi: 10.1021/acs.jmedchem.4c02792. Epub 2025 Feb 4.
Ubiquitin-specific protease 1 (USP1), a well-known member of the deubiquitinating enzymes, serves as a key regulator in DNA damage repair (DDR) processes. Herein, we utilized ring-opening and cyclization strategies based on KSQ-4279 to design a novel series of USP1 inhibitors featuring a morpholine scaffold. Notably, compound exhibited a more potent enzymatic and cellular inhibition activity compared to KSQ-4279. Mechanistically, was characterized as a selective, reversible, and noncompetitive USP1 inhibitor. efficiently activated the DDR pathway, induced cell cycle arrest and cell apoptosis, and inhibited cell survival. Importantly, it enhanced the sensitivity of olaparib-resistant cells to olaparib and showed a synergetic effect with andrographolide in BRCA-proficient cancer cells. Furthermore, had favorable pharmacokinetic profiles and good safety properties and . In the MDA-MB-436 xenograft model, displayed significant, dose-dependent antitumor efficacy. Overall, these findings indicate that is a promising lead compound for further drug development.
泛素特异性蛋白酶1（USP1）是去泛素化酶中一个著名的成员，在DNA损伤修复（DDR）过程中作为关键调节因子发挥作用。在此，我们基于KSQ - 4279利用开环和环化策略设计了一系列以吗啉骨架为特征的新型USP1抑制剂。值得注意的是，与KSQ - 4279相比，化合物表现出更强的酶抑制活性和细胞抑制活性。从机制上讲，被表征为一种选择性、可逆且非竞争性的USP1抑制剂。有效激活DDR通路，诱导细胞周期停滞和细胞凋亡，并抑制细胞存活。重要的是，它增强了奥拉帕尼耐药细胞对奥拉帕尼的敏感性，并在BRCA功能正常的癌细胞中与穿心莲内酯显示出协同作用。此外，具有良好的药代动力学特征和良好的安全性 以及 。在MDA - MB - 436异种移植模型中，显示出显著的、剂量依赖性的抗肿瘤疗效。总体而言，这些发现表明 是进一步药物开发的有前景的先导化合物。
