2. Academic Validation
  3. Discovery of a novel USP10 inhibitor with improved aqueous solubility for the treatment of hepatocellular carcinoma

Discovery of a novel USP10 inhibitor with improved aqueous solubility for the treatment of hepatocellular carcinoma

  • Bioorg Chem. 2026 Feb:169:109348. doi: 10.1016/j.bioorg.2025.109348.
Wentao Wang 1,  Mengxin Luo 1,  Chenxi Wang 1,  Yang Lu 2,  Peipei Wang 3,  Liuzhi Hu 1,  Bizhi Li 1,  Cheng Yuan 1,  Yubo Zhou 4,  Jinxin Che 5,  Xiaowu Dong 6
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 2 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.
  • 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: [email protected].
  • 6 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: [email protected].
PMID: 41443012 DOI: 10.1016/j.bioorg.2025.109348
Abstract

Ubiquitin-Specific Protease 10 (USP10) has emerged as an attractive target for Cancer therapy. Building upon our previously identified lead compound, LY-2, this study reports the discovery of WW-104, a USP10 inhibitor exhibiting enhanced solubility and potent enzymatic activity. Surface plasmon resonance and enzymatic assays delineated its binding mode and demonstrated appreciable selectivity for USP10 over USP7. WW-104 significantly suppressed the proliferation and colony formation of hepatocellular carcinoma cells and induced G2-phase arrest accompanied by Apoptosis. Moreover, this work provides a practical solubility determination protocol that may facilitate future optimization of the drug-like properties of Deubiquitinase inhibitors.

Keywords

Deubiquitinases; Hepatocellular carcinoma; Solubility; Ubiquitin-specific protease 10.

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