2. Academic Validation
  3. 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

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

  • Bioorg Med Chem. 2022 Dec 1:75:117072. doi: 10.1016/j.bmc.2022.117072.
Siddhi Chitre 1,  Anne-Marie Ray 1,  Mckayla Stevens 1,  Emma H Doud 1,  Hope Liechty 1,  Alex Washburn 1,  Katelyn Tepper 1,  Jared Sivinski 2,  Heather M O'Hagan 3,  Millie M Georgiadis 1,  Eli Chapman 2,  Steven M Johnson 4
Affiliations

Affiliations

  • 1 Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States.
  • 2 The University of Arizona, College of Pharmacy, Department of Pharmacology and Toxicology, 1703 E. Mabel St., PO Box 210207, Tucson, AZ 85721, United States.
  • 3 Indiana University School of Medicine, Medical Sciences Program and Department of Medical and Molecular Genetics, 1001 East 3rd St., Bloomington, IN 47405, United States.
  • 4 Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States. Electronic address: johnstm@iu.edu.
PMID: 36356534 DOI: 10.1016/j.bmc.2022.117072
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.

Keywords

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

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