Selective Inhibitor of Proteasome's Caspase-Like Sites Sensitizes Cells to Specific Inhibition of Chymotrypsin-Like Sites

Chem Biol. 2009 Dec 24;16(12):1278-89. doi: 10.1016/j.chembiol.2009.11.015.


Proteasomes degrade most proteins in mammalian cells and are established targets of anticancer drugs. All eukaryotic proteasomes have three types of active sites: chymotrypsin-like, trypsin-like, and caspase-like. Chymotrypsin-like sites are the most important in protein degradation and are the primary target of most proteasome inhibitors. The biological roles of trypsin-like and caspase-like sites and their potential as cotargets of antineoplastic agents are not well defined. Here we describe the development of site-specific inhibitors and active-site probes of chymotrypsin-like and caspase-like sites. Using these compounds, we show that cytotoxicity of proteasome inhibitors does not correlate with inhibition of chymotrypsin-like sites and that coinhibition of either trypsin-like and/or caspase-like sites is needed to achieve maximal cytotoxicity. Thus, caspase-like and trypsin-like sites must be considered as cotargets of anticancer drugs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / toxicity
  • Caspases / metabolism
  • Catalytic Domain
  • Cell Line
  • Chymotrypsin / metabolism
  • Humans
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / toxicity
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors*
  • Ubiquitin / metabolism


  • Antineoplastic Agents
  • Protease Inhibitors
  • Proteasome Inhibitors
  • Ubiquitin
  • Chymotrypsin
  • Caspases
  • Proteasome Endopeptidase Complex