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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.

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|January 29, 2020
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Summary
This summary is machine-generated.

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.

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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.