Exploiting the HSP60/10 chaperonin system as a chemotherapeutic target for colorectal cancer

Bioorg Med Chem. 2021 Jun 15;40:116129. doi: 10.1016/j.bmc.2021.116129. Epub 2021 Apr 19.


Over the past few decades, an increasing variety of molecular chaperones have been investigated for their role in tumorigenesis and as potential chemotherapeutic targets; however, the 60 kDa Heat Shock Protein (HSP60), along with its HSP10 co-chaperone, have received little attention in this regard. In the present study, we investigated two series of our previously developed inhibitors of the bacterial homolog of HSP60/10, called GroEL/ES, for their selective cytotoxicity to cancerous over non-cancerous colorectal cells. We further developed a third "hybrid" series of analogs to identify new candidates with superior properties than the two parent scaffolds. Using a series of well-established HSP60/10 biochemical screens and cell-viability assays, we identified 24 inhibitors (14%) that exhibited > 3-fold selectivity for targeting colorectal cancer over non-cancerous cells. Notably, cell viability EC50 results correlated with the relative expression of HSP60 in the mitochondria, suggesting a potential for this HSP60-targeting chemotherapeutic strategy as emerging evidence indicates that HSP60 is up-regulated in colorectal cancer tumors. Further examination of five lead candidates indicated their ability to inhibit the clonogenicity and migration of colorectal cancer cells. These promising results are the most thorough analysis and first reported instance of HSP60/10 inhibitors being able to selectively target colorectal cancer cells and highlight the potential of the HSP60/10 chaperonin system as a viable chemotherapeutic target.

Keywords: Chaperonin; Chemotherapeutic; Colorectal cancer; GroEL; GroES; HSP10; HSP60; Molecular chaperone; Proteostasis; Small molecule inhibitors.

Publication types

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

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Benzoxazoles / chemical synthesis
  • Benzoxazoles / chemistry
  • Benzoxazoles / pharmacology*
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Chaperonin 10 / antagonists & inhibitors*
  • Chaperonin 10 / metabolism
  • Chaperonin 60 / antagonists & inhibitors*
  • Chaperonin 60 / metabolism
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Salicylanilides / chemical synthesis
  • Salicylanilides / chemistry
  • Salicylanilides / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Benzoxazoles
  • Chaperonin 10
  • Chaperonin 60
  • Salicylanilides
  • salicylanilide