2. Academic Validation
  3. Discovery and Optimization of Novel Tricyclic Ubiquitin-Specific Protease 1 Inhibitors for the Treatment of BRCA-Mutated Breast Cancer

Discovery and Optimization of Novel Tricyclic Ubiquitin-Specific Protease 1 Inhibitors for the Treatment of BRCA-Mutated Breast Cancer

  • J Med Chem. 2025 Dec 25;68(24):25844-25865. doi: 10.1021/acs.jmedchem.5c01221.
Tianning Xiong 1 2 3,  Hong Yang 1 4,  Songwen Lin 1 2 3,  Li Sheng 1,  Junpu Ge 1,  Jinhua Wang 1 4,  Heng Xu 1 2 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 2 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 3 CAMS Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China.
  • 4 Beijing Key Laboratory of Innovative Drug Discovery and Polymorphic Druggability Research for Cerebrovascular Diseases, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China.
PMID: 41347736 DOI: 10.1021/acs.jmedchem.5c01221
Abstract

Ubiquitin-Specific Protease 1 (USP1) represents an emerging therapeutic target for BRCA-deficient malignancies. Using a scaffold-hopping strategy derived from KSQ-4279, we designed a novel series of USP1 inhibitors featuring a tricyclic core. Among them, two lead compounds 43 and 47 were identified with potent USP1 inhibitory and cellular antiproliferative activity. Further studies in MDA-MB-436 cells demonstrated that compounds 43 and 47 suppressed colony formation and induced S-phase arrest, with time- and concentration-dependently stabilizing ubiquitinated PCNA and amplifying p-H2AX. Importantly, both compounds showed synergistic antiproliferative effects in combination with the PARP Inhibitor Olaparib. Supported by its favorable pharmacokinetic properties, compound 43 exhibited significant in vivo Anticancer efficacy in an MDA-MB-436 xenograft model, achieving superior tumor growth inhibition both as monotherapy and in combination with Olaparib compared to KSQ-4279. Collectively, compound 43 emerges as a promising preclinical candidate with translational potential for BRCA-mutated breast Cancer.

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