2. Academic Validation
  3. Discovery of Potent Small-Molecule USP8 Inhibitors for the Treatment of Breast Cancer through Regulating ERα Expression

Discovery of Potent Small-Molecule USP8 Inhibitors for the Treatment of Breast Cancer through Regulating ERα Expression

  • J Med Chem. 2022 Jul 14;65(13):8914-8932. doi: 10.1021/acs.jmedchem.2c00013.
Yucheng Tian 1,  Kang Liu 1,  Ruoyi Liu 1,  Zhixia Qiu 1,  Yifan Xu 1,  Wei Wei 1,  Xi Xu 1,  Jubo Wang 1,  Hong Ding 2,  Zhiyu Li 1,  Jinlei Bian 1
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing210009, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Material Medical, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai201203, China.
PMID: 35786929 DOI: 10.1021/acs.jmedchem.2c00013
Abstract

Ubiquitin-Specific Protease 8 (USP8), belonging to the Deubiquitinase family, has been implicated to be closely related to the occurrence of many malignant tumors, but only a few USP8-targeting inhibitors have been reported to date. In this study, we present virtual screening to discover novel hit candidates that inhibit the catalytic activity of USP8. Exploration of the structure-activity relationship led to the identification of compound DC-U4106, which binds to USP8 with a KD value of 4.7 μM and is selective over USP2 and USP7. Western blotting and immunoprecipitation showed that DC-U4106 could target the ubiquitin pathway and facilitate the degradation of ERα. In a xenograft tumor model, DC-U4106 also significantly inhibited tumor growth with minimal toxicity. Overall, our findings suggest that DC-U4106 is a promising drug candidate and targeting the USP8-ERα complex could be a new approach to treat ER-positive or drug-resistant breast Cancer.

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