Design and Synthesis of USP1 Inhibitors: Synergistic Antitumor Activity with PARP Inhibitors in Triple-Negative Breast Cancer

  • J Med Chem. 2026 May 14;69(9):10594-10620. doi: 10.1021/acs.jmedchem.5c03804.
Yaxin Teng  1 ,  Linyu Yang  1 ,  Haoyue Luo  1 ,  Minghai Tang  1 ,  Jialing Song  1 ,  Liping Gou  2 ,  Yuzhou Xiao  1 ,  Xue Cui  1 ,  Tao Yang  3 ,  Xiaobo Cen  3  4 ,  Lijuan Chen  1 ,  Yong Li  5 ,  Yinglan Zhao  1 ,  Zhuang Yang  1
Affiliations
  • 1. Laboratory of Natural and Targeted Small Molecule Drugs, Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
  • 2. Department of Endocrinology and Metabolism, Center for Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3. National Chengdu Center for Safety Evaluation of Drugs, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 4. West China-Frantier PharmaTech Co., Ltd., Chengdu 610200, China.
  • 5. Innovation Center of Nursing Research and Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, West ChinaHospital, Sichuan University, West China School of Nursing, Sichuan University, Chengdu 610041, Sichuan, China.
PMID: 42054575 DOI: 10.1021/acs.jmedchem.5c03804
Abstract

Ubiquitin-Specific Protease 1 (USP1) regulates the DNA damage response (DDR) by deubiquitinating PCNA, and its inhibition potentiates PARP Inhibitor efficacy, highlighting USP1 as a promising therapeutic target in triple-negative breast Cancer (TNBC). Guided by USP1-UAF1 structural insights, we optimized the KSQ-4279 scaffold and identified 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one as a scaffold-hopping core for proof-of-concept exploration. Representative compound 57 exhibited nanomolar USP1-UAF1 inhibition, antiproliferative activity against MDA-MB-436 cells, favorable human liver microsomal stability, and 76% oral bioavailability in rats. In vitro assays and in vivo xenograft studies demonstrated synergistic antitumor activity between compound 57 and Olaparib, resulting in DNA damage and significantly enhanced tumor growth inhibition compared with Olaparib monotherapy. Transcriptomic analysis and Western blot results further supported enhanced suppression of tumor survival pathways. Collectively, this work establishes compound 57 as a scaffold-hopping, proof-of-concept USP1 Inhibitor and provides in vivo validation for USP1-PARP inhibitor combination therapy in TNBC.

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