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
  • 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.

Products