2. Academic Validation
  3. Discovery of potent small molecule ubiquitin-specific protease 10 inhibitors with anti-hepatocellular carcinoma activity through regulating YAP expression

Discovery of potent small molecule ubiquitin-specific protease 10 inhibitors with anti-hepatocellular carcinoma activity through regulating YAP expression

  • Eur J Med Chem. 2024 Jun 5:272:116468. doi: 10.1016/j.ejmech.2024.116468.
Yang Lu 1,  Jian Gao 1,  Peipei Wang 2,  Haifeng Chen 1,  Xinjun He 1,  Mengxin Luo 1,  Yu Guo 1,  Linjie Li 1,  Weihao Zhuang 1,  Bo Zhang 3,  Nengming Lin 3,  Jia Li 4,  Yubo Zhou 5,  Xiaowu Dong 6,  Jinxin Che 7
Affiliations

Affiliations

  • 1 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 3 Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China; Cancer Center, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Guangdong, 528400, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Guangdong, 528400, China.
  • 6 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Department of Pharmacy, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China; Cancer Center, Zhejiang University, Hangzhou, 310058, China; National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, 310058, China. Electronic address: dongxw@zju.edu.cn.
  • 7 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, 310058, China. Electronic address: chejx@zju.edu.cn.
PMID: 38718626 DOI: 10.1016/j.ejmech.2024.116468
Abstract

High expression of Ubiquitin-Specific Protease 10 (USP10) promote the proliferation of hepatocellular carcinoma (HCC), thus the development of USP10 inhibitors holds promise as a novel therapeutic approach for HCC treatment. However, the development of selective USP10 inhibitor is still limited. In this study, we developed a novel USP10 inhibitor for investigating the feasibility of targeting USP10 for the treatment of HCC. Due to high USP10 inhibition potency and prominent selectivity, compound D1 bearing quinolin-4(1H)-one scaffold was identified as a lead compound. Subsequent research revealed that D1 significantly inhibits cell proliferation and clone formation in HCC cells. Mechanistic insights indicated that D1 targets the ubiquitin pathway, facilitating the degradation of YAP (Yes-associated protein), thereby triggering the downregulation of p53 and its downstream protein p21. Ultimately, this cascade leads to S-phase arrest in HCC cells, followed by cell Apoptosis. Collectively, our findings highlight D1 as a promising starting point for USP10-positive HCC treatment, underscoring its potential as a vital tool for unraveling the functional intricacies of USP10.

Keywords

Deubiquitination; Hepatocellular carcinoma; Selectivity; Ubiquitin-specific protease 10.

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