Selective and cell-active inhibitors of the USP1/ UAF1 deubiquitinase complex reverse cisplatin resistance in non-small cell lung cancer cells.

Therapeutic Approaches


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.


Chen, Junjun; Dexheimer, Thomas S; Ai, Yongxing; Liang, Qin; Villamil, Mark A; Inglese, James; Maloney, David J; Jadhav, Ajit; Simeonov, Anton; Zhuang, Zhihao;


  • Antineoplastic Agents/ pharmacology
  • Arabidopsis Proteins
  • Butyrates/ pharmacology
  • Carcinoma, Non-Small-Cell Lung/ enzymology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cisplatin/ pharmacology
  • DNA Repair
  • Drug Resistance, Neoplasm
  • Endopeptidases/ chemistry
  • Endopeptidases/ metabolism
  • Fanconi Anemia/ metabolism
  • Humans
  • Kinetics
  • Nuclear Proteins/ antagonists & inhibitors
  • Nuclear Proteins/ metabolism
  • Phenylurea Compounds/ pharmacology
  • Pimozide/ pharmacology
  • Ubiquitin/ metabolism
  • Ubiquitin-Specific Proteases

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