Selective and Cell-Active Inhibitors of the USP1/ UAF1 Deubiquitinase Complex Reverse Cisplatin Resistance in Non-small Cell Lung Cancer Cells

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 full-size imageDownload 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