Bis-aryl-α,β-unsaturated ketone (ABK) chaperonin inhibitors exhibit selective cytotoxicity to colorectal cancer cells that correlates with levels of aberrant HSP60 in the cytosol

Siddhi Chitre, Anne Marie Ray, Mckayla Stevens, Emma H. Doud, Hope Liechty, Alex Washburn, Katelyn Tepper, Jared Sivinski, Heather M. O'Hagan, Millie M. Georgiadis, Eli Chapman, Steven M. Johnson

Research output: Contribution to journalArticlepeer-review

Abstract

While many studies have established the importance of protein homeostasis in tumor progression, little effort has been made to examine the therapeutic potential of targeting the HSP60 chaperonin system. In healthy cells, HSP60 is localized to the mitochondrial matrix; however, emerging evidence indicates HSP60 can be over-expressed and mis-localized to the cytosol of cancer cells, which is hypothesized to promote tumor cell survival and proliferation. This opens a potential avenue to selectively target the aberrant HSP60 in the cytosol as a chemotherapeutic strategy. In the present work, we examined a series of bis-aryl-α,β-unsaturated ketone (ABK) HSP60 inhibitors for their ability to selectively target cancerous vs non-cancerous colon and intestine cells. We found that lead analogs inhibited migration and clonogenicity of cancer cells, with cytotoxicity correlating with the level of aberrant HSP60 in the cytosol.

Original languageEnglish (US)
Article number117072
JournalBioorganic and Medicinal Chemistry
Volume75
DOIs
StatePublished - Dec 1 2022

Keywords

  • Chaperonin
  • Chemotherapeutics
  • Colorectal cancer
  • Hsp10
  • HSP60
  • HSPD1
  • Molecular chaperone
  • Proteostasis
  • Small molecule inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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