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Targeting cavity-creating p53 cancer mutations with small-molecule stabilizers: the Y220X paradigm

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posted on 2023-06-09, 20:37 authored by Matthias R Bauer, Andreas Krämer, Giovanni Settanni, Rhiannon N Jones, Xiaomin Ni, Raysa Khan, Alan R Fersht, John SpencerJohn Spencer, Andreas C Joerger
We have previously shown that the thermolabile, cavity-creating p53 cancer mutant Y220C can be reactivated by small-molecule stabilizers. In our ongoing efforts to unearth druggable variants of the p53 mutome, we have now analyzed the effects of other cancer-associated mutations at codon 220 on the structure, stability and dynamics of the p53 DNA-binding domain (DBD). We found that the oncogenic Y220H, Y220N and Y220S mutations are also highly destabilizing, suggesting that they are largely unfolded under physiological conditions. A high-resolution crystal structure of the Y220S mutant DBD revealed a mutation-induced surface crevice similar to that of Y220C, whereas the corresponding pocket’s accessibility to small molecules was blocked in the structure of the Y220H mutant. Accordingly, a series of carbazole-based small molecules, designed for stabilizing the Y220C mutant, also bound to and stabilized the folded state of the Y220S mutant, albeit with varying affinities due to structural differences in the binding pocket of the two mutants. Some of the compounds also bound to and stabilized the Y220N mutant, but not the Y220H mutant. Our data validate the Y220S and Y220N mutant as druggable targets and provide a framework for the design of Y220S or Y220N-specific compounds as well as compounds with dual Y220C/Y220S specificity for use in personalized cancer therapy

Funding

Rescuing p53 Function in Cancer. Targeting the Y220C Mutation; G2344; WORLDWIDE CANCER RESEARCH; 18-0043

History

Publication status

  • Published

File Version

  • Accepted version

Journal

ACS Chemical Biology

ISSN

1554-8929

Publisher

American Chemical Society

Department affiliated with

  • Chemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2020-02-17

First Open Access (FOA) Date

2021-01-29

First Compliant Deposit (FCD) Date

2020-02-14

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