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

DOI: 10.1021/acschembio.9b00748

Authors: Matthias Bauer (MRC Laboratory of Molecular Biology) , Andreas Krämer (Johann Wolfgang Goethe University; Buchmann Institute for Molecular Life Sciences; Structural Genomics Consortium (SGC)) , Giovanni Settanni (Johannes Gutenberg University) , Rhiannon N Jones (University of Sussex) , Xiaomin Ni (Johann Wolfgang Goethe University; Buchmann Institute for Molecular Life Sciences; Structural Genomics Consortium (SGC)) , Raysa Khan Tareque (University of Sussex) , Alan R. Fersht (MRC Laboratory of Molecular Biology) , John Spencer (University of Sussex) , Andreas C. Joerger (Johann Wolfgang Goethe University; Buchmann Institute for Molecular Life Sciences; Structural Genomics Consortium (SGC))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Chemical Biology

State: Published (Approved)
Published: January 2020

Abstract: 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.

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography

Other Facilities: Swiss Light Source

Added On: 03/02/2020 10:51

Documents:
acschembio.9b00748.pdf

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Cancer Drug Discovery Non-Communicable Diseases Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)