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
  • 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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