噻唑衍生物作为新型USP7抑制剂的合成及生物学评价
Synthesis and biological evaluation of thiazole derivatives as novel USP7 inhibitors.
作者信息
Chen Chao, Song Jiemei, Wang Jinzheng, Xu Chang, Chen Caiping, Gu Wei, Sun Hongbin, Wen Xiaoan
机构信息
Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China.
Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
出版信息
Bioorg Med Chem Lett. 2017 Feb 15;27(4):845-849. doi: 10.1016/j.bmcl.2017.01.018. Epub 2017 Jan 10.
Herpesvirus-associated Ubiquitin-Specific Protease (HAUSP, also called USP7) interacts with and stabilizes Mdm2, and represents one of the first examples that deubiquitinases oncogenic proteins. USP7 has been regarded as a potential drug target for cancer therapy. Inhibitors of USP7 have been recently shown to suppress tumor cell growth in vitro and in vivo. Based on leading USP7 inhibitors P5091 and P22077, we designed and synthesized a series of thiazole derivatives. The results of in vitro assays showed that the thiazole compounds exhibited low micromolar inhibition activity against both USP7 enzyme and cancer cell lines. The compounds induced cell death in a p53-dependent and p53-independent manner. Taken together, this study may provide thiazole compounds as a new class of USP7 inhibitors.
疱疹病毒相关泛素特异性蛋白酶（HAUSP，也称为USP7）与Mdm2相互作用并使其稳定，是去泛素化酶作用于致癌蛋白的首批实例之一。USP7被视为癌症治疗的潜在药物靶点。最近研究表明，USP7抑制剂可在体外和体内抑制肿瘤细胞生长。基于主要的USP7抑制剂P5091和P22077，我们设计并合成了一系列噻唑衍生物。体外试验结果表明，这些噻唑化合物对USP7酶和癌细胞系均表现出低微摩尔抑制活性。这些化合物以p53依赖和p53非依赖的方式诱导细胞死亡。综上所述，本研究可能为新型USP7抑制剂——噻唑化合物的开发提供依据。
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