title: Selective and cell-active inhibitors of the USP1/ UAF1 deubiquitinase complex reverse cisplatin resistance in non-small cell lung cancer cells.
abstract: 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.
authors: Department of Chemistry and Biochemistry, 214A Drake Hall, University of Delaware, Newark, DE 19716, USA.
authors: Junjun
authors: J
authors: Chen
authors: Thomas S
authors: TS
authors: Dexheimer
authors: Yongxing
authors: Y
authors: Ai
authors: Qin
authors: Q
authors: Liang
authors: Mark A
authors: MA
authors: Villamil
authors: James
authors: J
authors: Inglese
authors: David J
authors: DJ
authors: Maloney
authors: Ajit
authors: A
authors: Jadhav
authors: Anton
authors: A
authors: Simeonov
authors: Zhihao
authors: Z
authors: Zhuang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D029681:Arabidopsis Proteins; D002087:Butyrates / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology*; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm; D010450:Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D005199:Fanconi Anemia / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000494:pharmacology; D010868:Pimozide / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases
chemical_list: D000970:Antineoplastic Agents; D029681:Arabidopsis Proteins; D002087:Butyrates; D002945:Cisplatin; D010450:Endopeptidases; D009687:Nuclear Proteins; D010671:Phenylurea Compounds; D010868:Pimozide; D025801:Ubiquitin; D064570:Ubiquitin-Specific Proteases; C453899:GW 7647; C526165:WDR48 protein, human; C579228:USP1 protein, human