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
文献类型：期刊论文
| 作者 | Lu, Yang1,2; Wang, Wentao2; Yuan, Cheng2; Luo, Mengxin2; Wang, Peipei3,4; Li, Bizhi2; Hu, Liuzhi2; Shen, Zheyuan2; Zhou, Yubo3; Che, Jinxin2 |
| 刊名 | BIOORGANIC CHEMISTRY
 |
| 出版日期 | 2025-08-01 |
| 卷号 | 163页码:17 |
| 关键词 | HCC USP10 Deubiquitination Binding affinity CDK4 |
| ISSN号 | 0045-2068 |
| DOI | 10.1016/j.bioorg.2025.108775 |
| 英文摘要 | 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. |
| WOS关键词 | HETEROCYCLIC REPLACEMENT ; DEUBIQUITINATION ; USP10 ; ACTIVATION ; P53 |
| 资助项目 | Key R&D Program of Zhejiang Province ; National Natural Science Foundation of China |
| WOS研究方向 | Biochemistry & Molecular Biology ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001543159400002 |
| 出版者 | ACADEMIC PRESS INC ELSEVIER SCIENCE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/321189]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Che, Jinxin; Dong, Xiaowu |
| 作者单位 | 1.Hangzhou City Univ, Sch Med, Key Lab Novel Targets & Drug Study Neural Repair Z, Hangzhou 310015, Peoples R China 2.Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou 310058, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China |
| 推荐引用方式 GB/T 7714 | Lu, Yang,Wang, Wentao,Yuan, Cheng,et al. 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[J]. BIOORGANIC CHEMISTRY,2025,163:17. |
| APA | Lu, Yang.,Wang, Wentao.,Yuan, Cheng.,Luo, Mengxin.,Wang, Peipei.,...&Dong, Xiaowu.(2025).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.BIOORGANIC CHEMISTRY,163,17. |
| MLA | Lu, Yang,et al."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".BIOORGANIC CHEMISTRY 163(2025):17. |
入库方式： OAI收割
来源：上海药物研究所
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