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Targeting Cavity-Creating p53 Cancer Mutations with Small-Molecule Stabilizers: the Y220X Paradigm
journal contribution
posted on 2020-02-21, 14:54 authored by Matthias
R. Bauer, Andreas Krämer, Giovanni Settanni, Rhiannon N. Jones, Xiaomin Ni, Raysa Khan Tareque, Alan R. Fersht, John Spencer, Andreas C. JoergerWe 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 mutants 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.