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Updated: Jul 10, 2026

Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

A Tale of Two Mechanisms: The p53 Modulator COTI-2 Is a Zn Metallochaperone

İrem Şimşek1, Farsheed Shahbazi-Raz1,2, Michael J Krause1

  • 1Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.

Drug Development Research
|July 9, 2026
PubMed

Insights

COTI-2, a cancer drug, does not refold mutant p53 directly. Instead, it acts as a zinc chaperone, restoring function by replacing lost zinc ions in p53 mutants.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • TP53 mutations are prevalent in ~50% of human cancers, leading to loss of tumor suppressor function.
  • The p53 protein is crucial for inducing apoptosis in cells with DNA damage.
  • Small molecules are being investigated to restore p53 conformation and activity.

Purpose of the Study:

  • To investigate the mechanism of action of COTI-2, a thiosemicarbazone with demonstrated anti-cancer properties.
  • To determine if COTI-2 directly refolds mutant p53 or acts through an alternative pathway.
  • To elucidate the role of zinc in COTI-2's interaction with p53.

Main Methods:

  • Utilized a combination of experimental assays, including cell-based studies.
  • Employed computational approaches to model molecular interactions.
  • Analyzed transcriptomics data to assess cellular responses to COTI-2.

Main Results:

  • Experimental and computational data suggest COTI-2 does not directly refold mutant p53.
  • COTI-2 functions as a selective zinc chaperone.
  • The drug replaces zinc ions lost from p53 mutants with deficient zinc-binding.

Conclusions:

  • The primary mechanism of COTI-2 involves acting as a zinc chaperone, not direct p53 refolding.
  • This zinc-chaperoning activity likely underlies its efficacy against cancers with p53 mutations.
  • COTI-2 represents a promising therapeutic strategy for cancers harboring p53 alterations.
Keywords:
apoptosischemotherapymetallochaperonepersonalized medicinerestoration‐of‐function

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