2. Academic Validation
  3. Discovery of a ubiquitin-specific protease 10 inhibitor with high binding affinity promoting cell apoptosis via down-regulated CDK4 for the treatment of hepatocellular carcinoma

Discovery of a ubiquitin-specific protease 10 inhibitor with high binding affinity promoting cell apoptosis via down-regulated CDK4 for the treatment of hepatocellular carcinoma

  • Bioorg Chem. 2025 Aug:163:108775. doi: 10.1016/j.bioorg.2025.108775.
Yang Lu 1,  Wentao Wang 2,  Cheng Yuan 2,  Mengxin Luo 2,  Peipei Wang 3,  Bizhi Li 2,  Liuzhi Hu 2,  Zheyuan Shen 2,  Yubo Zhou 4,  Jinxin Che 5,  Xiaowu Dong 6
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou 310015, China.
  • 2 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 3 State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 4 State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: chejx@zju.edu.cn.
  • 6 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: dongxw@zju.edu.cn.
PMID: 40729788 DOI: 10.1016/j.bioorg.2025.108775
Abstract

Ubiquitin-Specific Protease 10 (USP10) has been associated with unfavorable prognoses in hepatocellular carcinoma (HCC) and represents a promising therapeutic target. However, current USP10 inhibitors demonstrate limited binding affinity and efficacy, highlighting the urgent need for novel compounds. This study builds upon the previously identified USP10 inhibitor D1 and introduces compound LY-2, which exhibits significantly enhanced binding affinity compared to D1, thereby establishing it as a promising candidate through comprehensive structure-activity relationship (SAR) analysis. In vitro experiments reveal that LY-2 is the first USP10 inhibitor to achieve nanomolar-level binding affinity, with Phe629 and Thr630 identified as critical residues for this interaction. Furthermore, LY-2 effectively inhibits USP10-mediated proteasomal degradation of downstream proteins YAP and p53, leading to the subsequent downregulation of CDK4 in the p53 signaling pathway. This action promotes Apoptosis in HCC cells and inhibits the onset and progression of liver Cancer. These chemical probes will facilitate further exploration of the roles of USP10 in HCC and Other Diseases.

Keywords

Binding affinity; CDK4; Deubiquitination; HCC; USP10.

Figures
Products