Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing210009, China.
State Key Laboratory of Drug Research, Shanghai Institute of Material Medical, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai201203, China.
J Med Chem. 2022 Jul 14;65(13):8914-8932. doi: 10.1021/acs.jmedchem.2c00013. Epub 2022 Jul 5.
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 , which binds to USP8 with a value of 4.7 μM and is selective over USP2 and USP7. Western blotting and immunoprecipitation showed that could target the ubiquitin pathway and facilitate the degradation of ERα. In a xenograft tumor model, also significantly inhibited tumor growth with minimal toxicity. Overall, our findings suggest that 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.
泛素特异性蛋白酶 8（USP8）属于去泛素化酶家族，与许多恶性肿瘤的发生密切相关，但迄今为止仅报道了少数 USP8 靶向抑制剂。在这项研究中，我们进行了虚拟筛选，以发现抑制 USP8 催化活性的新型命中候选物。对构效关系的探索导致了化合物 的鉴定，其与 USP8 的结合 值为 4.7 μM，对 USP2 和 USP7 具有选择性。Western blotting 和免疫沉淀表明， 可以靶向泛素途径并促进 ERα 的降解。在异种移植肿瘤模型中， 也显著抑制肿瘤生长，且毒性最小。总的来说，我们的研究结果表明， 是一种很有前途的药物候选物，针对 USP8-ERα 复合物可能是治疗 ER 阳性或耐药性乳腺癌的新方法。
