Chen Junjun, Dexheimer Thomas S, Ai Yongxing, Liang Qin, Villamil Mark A, Inglese James, Maloney David J, Jadhav Ajit, Simeonov Anton, Zhuang Zhihao
Department of Chemistry and Biochemistry, 214A Drake Hall, University of Delaware, Newark, DE 19716, USA.
Chem Biol. 2011 Nov 23;18(11):1390-400. doi: 10.1016/j.chembiol.2011.08.014.
Ubiquitin-specific proteases (USPs) have in recent years emerged as a promising therapeutic target class. We identified selective small-molecule inhibitors against a deubiquitinase complex, the human USP1/UAF1, through quantitative high throughput screening (qHTS) of a collection of bioactive molecules. The top inhibitors, pimozide and GW7647, inhibited USP1/UAF1 noncompetitively with a K(i) of 0.5 and 0.7 μM, respectively, and displayed selectivity against a number of deubiquitinases, deSUMOylase, and cysteine proteases. The USP1/UAF1 inhibitors act synergistically with cisplatin in inhibiting cisplatin-resistant non-small cell lung cancer (NSCLC) cell proliferation. USP1/UAF1 represents a promising target for drug intervention because of its involvement in translesion synthesis and Fanconi anemia pathway important for normal DNA damage response. Our results support USP1/UAF1 as a potential therapeutic target and provide an example of targeting the USP/WD40 repeat protein complex for inhibitor discovery.
泛素特异性蛋白酶（USPs）近年来已成为一类很有前景的治疗靶点。我们通过对一系列生物活性分子进行定量高通量筛选（qHTS），鉴定出了针对一种去泛素化酶复合物——人USP1/UAF1的选择性小分子抑制剂。顶级抑制剂匹莫齐特和GW7647以非竞争性方式抑制USP1/UAF1，其抑制常数（K(i)）分别为0.5和0.7 μM，并对多种去泛素化酶、去SUMO化酶和半胱氨酸蛋白酶表现出选择性。USP1/UAF1抑制剂与顺铂协同作用，抑制顺铂耐药的非小细胞肺癌（NSCLC）细胞增殖。USP1/UAF1因其参与对正常DNA损伤反应很重要的跨损伤合成和范可尼贫血途径，而成为药物干预的一个有前景的靶点。我们的结果支持USP1/UAF1作为一个潜在的治疗靶点，并提供了一个针对USP/WD40重复蛋白复合物进行抑制剂发现的实例。
