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

  • J Med Chem. 2025 Feb 13;68(3):3673-3699. doi: 10.1021/acs.jmedchem.4c02792.
Junjie Zhang  1  2  3 ,  Benjin Liu  4  5 ,  Ruyue Ren  1  2  6 ,  Shanshan Song  4 ,  Xubin Bao  4 ,  Xiajuan Huan  4 ,  Hongrui Li  1  2 ,  Jiahao Xu  1  2 ,  Ting Yu  1  2 ,  Ruifeng Wang  6 ,  Ze-Hong Miao  4  5  3 ,  Bing Xiong  1  2  3 ,  Jinxue He  4  3 ,  Tongchao Liu  1  2
Affiliations
  • 1. Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China.
  • 2. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
  • 3. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, P. R. China.
  • 4. State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5. School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, China.
  • 6. School of Pharmacy, Shanxi Medical University, Taiyuan 030001, China.
PMID: 39902599 DOI: 10.1021/acs.jmedchem.4c02792
Abstract

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.

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