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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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


  • Antineoplastic Agents
  • Arabidopsis Proteins
  • Butyrates
  • GW 7647
  • Nuclear Proteins
  • Phenylurea Compounds
  • USP1 associated factor 1, human
  • Ubiquitin
  • Pimozide
  • Endopeptidases
  • USP1 protein, human
  • Ubiquitin-Specific Proteases
  • Cisplatin