Related Experiment Video

Updated: Aug 26, 2025

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

Published on: August 4, 2019

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A Small Molecule Reacts with the p53 Somatic Mutant Y220C to Rescue Wild-type Thermal Stability

Keelan Z Guiley1, Kevan M Shokat1

  • 1Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California.

Cancer Discovery
|October 5, 2022
PubMed

Insights

Researchers discovered a novel compound that targets the mutated p53 protein (tumor suppressor protein 53) by selectively reacting with a specific cysteine. This approach aims to restore the normal function of p53, a critical gene in cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • The p53 protein is a crucial tumor suppressor frequently inactivated in various cancers.
  • Mutations in p53 lead to uncontrolled cell growth and genomic instability, key cancer characteristics.
  • Current therapies do not directly address mutant p53 to restore its wild-type function.

Purpose of the Study:

  • To identify compounds that can selectively target and react with mutant p53.
  • To develop a therapeutic strategy that rescues wild-type p53 function.

Main Methods:

  • Screening for covalent compounds that interact with the p53 Y220C mutant.
  • Assessing the ability of identified compounds to restore wild-type p53 thermal stability and gene activation.

Main Results:

  • Identification of the first allele-specific compound targeting the p53 Y220C mutation.
  • Demonstration that the compound selectively reacts with mutant cysteine Y220C.
  • Restoration of wild-type thermal stability and gene activation of p53.

Conclusions:

  • This study presents a promising therapeutic strategy for cancers with p53 Y220C mutations.
  • The identified compound represents a potential first-in-class therapeutic targeting mutant p53.
  • Further development could lead to novel treatments for a significant proportion of human cancers.

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