Discovery and Optimization of a Series of Novel Morpholine-Containing USP1 Inhibitors

作者：Junjie Zhang, Benjin Liu, Ruyue Ren, Shanshan Song, Xubin Bao, Xia‐Juan Huan, Hongrui Li, Jiahao Xu, Ting Yu, Ruifeng Wang, Ze‐Hong Miao, Bing Xiong, Jin‐Xue He, Tongchao Liu · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.4c02792 · 被引用次数：10 · 研究领域：Ubiquitin and proteasome pathways、PARP inhibition in cancer therapy、Toxin Mechanisms and Immunotoxins

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 38-P2 exhibited a more potent enzymatic and cellular inhibition activity compared to KSQ-4279. Mechanistically, 38-P2 was characterized as a selective, reversible, and noncompetitive USP1 inhibitor. 38-P2 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, 38-P2 had favorable pharmacokinetic profiles and good safety properties in vitro and in vivo . In the MDA-MB-436 xenograft model, 38-P2 displayed significant, dose-dependent antitumor efficacy. Overall, these findings indicate that 38-P2 is a promising lead compound for further drug development.