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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Targeting Cavity-Creating p53 Cancer Mutations with Small-Molecule Stabilizers: the Y220X Paradigm

Matthias R Bauer1, Andreas Krämer2,3, Giovanni Settanni4

  • 1MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, United Kingdom.

ACS Chemical Biology
|January 29, 2020
PubMed

Insights

Small molecules can stabilize destabilized p53 cancer mutants. Researchers found that Y220S and Y220N p53 mutants are druggable targets, paving the way for new personalized cancer therapies.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Cancer Research

Background:

  • The p53 tumor suppressor protein is frequently mutated in cancer.
  • The p53 DNA-binding domain (DBD) can be destabilized by cancer-associated mutations, leading to loss of function.
  • Previous work demonstrated that small-molecule stabilizers can reactivate the Y220C p53 mutant.

Purpose of the Study:

  • To investigate the structural and dynamic effects of other cancer-associated mutations at codon 220 of p53.
  • To identify novel druggable p53 variants within the p53 mutome.
  • To explore the potential for small-molecule reactivation of these mutants.

Main Methods:

  • Analysis of p53 DNA-binding domain (DBD) structure, stability, and dynamics for Y220H, Y220N, and Y220S mutants.
  • High-resolution crystal structure determination of the Y220S mutant DBD.
  • Small-molecule screening using carbazole-based compounds designed for Y220C stabilization.

Main Results:

  • Y220H, Y220N, and Y220S mutations destabilize the p53 DBD, similar to Y220C.
  • The Y220S mutant exhibits a surface crevice amenable to small-molecule binding, while Y220H shows a blocked pocket.
  • Carbazole compounds stabilized Y220S and Y220N mutants, with varying affinities, and some also bound Y220N but not Y220H.

Conclusions:

  • The Y220S and Y220N p53 mutants are validated as druggable targets.
  • Structural insights guide the design of specific or dual-targeting small molecules for Y220C/Y220S mutants.
  • This research provides a framework for developing personalized cancer therapies by targeting specific p53 mutations.

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