کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1391914 | 983666 | 2011 | 11 صفحه PDF | دانلود رایگان |
SummaryUbiquitin-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 Ki 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.
Graphical AbstractFigure optionsDownload high-quality image (270 K)Download as PowerPoint slideHighlights
► Reversible inhibitors of the deubiquitinase complex USP1/UAF1 were identified
► The USP1/UAF1 inhibitors modulate the cellular level of Ub-PCNA and Ub-FANCD2
► Inhibitors reverse chemoresistance of nonsmall cell lung cancer cells to cisplatin
► The inhibitors represent a new use of existing drugs
Journal: - Volume 18, Issue 11, 23 November 2011, Pages 1390–1400