Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell line

Chem Biol. 2003 Sep;10(9):837-46. doi: 10.1016/j.chembiol.2003.08.010.


Neuronal ubiquitin C-terminal hydrolase (UCH-L1) has been linked to Parkinson's disease (PD), the progression of certain nonneuronal tumors, and neuropathic pain. Certain lung tumor-derived cell lines express UCH-L1 but it is not expressed in normal lung tissue, suggesting that this enzyme plays a role in tumor progression, either as a trigger or as a response. Small-molecule inhibitors of UCH-L1 would be helpful in distinguishing between these scenarios. By utilizing high-throughput screening (HTS) to find inhibitors and traditional medicinal chemistry to optimize their affinity and specificity, we have identified a class of isatin O-acyl oximes that selectively inhibit UCH-L1 as compared to its systemic isoform, UCH-L3. Three representatives of this class (30, 50, 51) have IC(50) values of 0.80-0.94 micro M for UCH-L1 and 17-25 micro M for UCH-L3. The K(i) of 30 toward UCH-L1 is 0.40 micro M and inhibition is reversible, competitive, and active site directed. Two isatin oxime inhibitors increased proliferation of the H1299 lung tumor cell line but had no effect on a lung tumor line that does not express UCH-L1. Inhibition of UCH-L1 expression in the H1299 cell line using RNAi had a similar proproliferative effect, suggesting that the UCH-L1 enzymatic activity is antiproliferative and that UCH-L1 expression may be a response to tumor growth. The molecular mechanism of this response remains to be determined.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Drug Evaluation, Preclinical / methods
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Isatin / chemistry
  • Isatin / pharmacology*
  • Isoenzymes / antagonists & inhibitors
  • Lung Neoplasms / pathology*
  • Oximes / chemistry
  • Oximes / pharmacology*
  • Structure-Activity Relationship
  • Ubiquitin Thiolesterase / antagonists & inhibitors*


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Isoenzymes
  • Oximes
  • Isatin
  • Ubiquitin Thiolesterase