The team of Zhiyu Li and Jinlei Bian has made great progress in the research of USP8 inhibitors and the relevant research was published in the Journal of Medicinal Chemistry under the title “Discovery of Potent Small-Molecule USP8 Inhibitors for the Treatment of Breast Cancer through Regulating ERα Expression” (DOI: 10.1021/acs.jmedchem.2c00013). Yucheng Tian completed this paper under the guidance of Professor Zhiyu Li and Jinlei Bian, and China Pharmaceutical University was the first communication unit.
Ubiquitin-specific protease 8 (USP8) can participate in the ubiquitin proteasome pathway, and its shear mutants often lead to the occurrence of malignant tumors. However, the unclear binding mode and mechanism of inhibitors have led to the slow progress of relevant research.
In this study, the team of Professor Li present a virtual screening to discover novel hit candidates that inhibits the catalytic activity of USP8. Exploration of the structure-activity relationship led to the identification of compound DC-U4106, which is selective over USP2 and USP7. The SPR-based binding assay and the activity-based protein profiling assay were also performed to determine the binding affinity of USP8. In addition, Western blotting and immunoprecipitation showed that DC-U4106 could target ubiquitin pathway and facilitate the degradation of ERα. In a xenograft tumor model, DC-U4106 showed significantly inhibited tumor growth with minimal toxicity compared with tamoxifen.
Overall, the relevant findings suggest that DC-U4106 is a promising drug candidate and targeting USP8-ERα complex could be a new approach to treat ER-positive or drug-resistant breast cancer.
This work was supported by the National Natural Science Foundation of China, the National Natural Science Foundation of Jiangsu Province of China and other projects.
