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A structure-guided molecular chaperone approach for restoring the transcriptional activity of the p53 cancer mutant Y220C
Version 2 2023-06-07, 08:27
Version 1 2023-06-07, 06:42
journal contribution
posted on 2023-06-07, 08:27 authored by Matthias Bauer, Alice Rhiannon Jones, Raysa Khan, Bradley Springett, Felix Dingler, Lorena Verduci, Ketan Patel, Alan Fersht, Andreas Joerger, John SpencerJohn SpencerAim: The p53 cancer mutation Y220C creates a conformationally unstable protein with a unique elongated surface crevice that can be targeted by molecular chaperones. We report the structure-guided optimization of the carbazole-based stabilizer PK083. Materials & methods: Biophysical, cellular and x-ray crystallographic techniques have been employed to elucidate the mode of action of the carbazole scaffolds. Results: Targeting an unoccupied subsite of the surface crevice with heterocycle-substituted PK083 analogs resulted in a 70-fold affinity increase to single-digit micromolar levels, increased thermal stability and decreased rate of aggregation of the mutant protein. PK9318, one of the most potent binders, restored p53 signaling in the liver cancer cell line HUH-7 with homozygous Y220C mutation. Conclusion: The p53-Y220C mutant is an excellent paradigm for the development of mutant p53 rescue drugs via protein stabilization. Similar rescue strategies may be applicable to other cavity-creating p53 cancer mutations.
Funding
Rescuing p53 Function in Cancer. Targeting the Y220C Mutation; G2344; WORLDWIDE CANCER RESEARCH; 18-0043
History
Publication status
- Published
File Version
- Published version
Journal
Future Medicinal ChemistryISSN
1756-8919Publisher
Future ScienceExternal DOI
Issue
19Volume
11Page range
2491-2504Department affiliated with
- Chemistry Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2019-08-19First Open Access (FOA) Date
2019-11-01First Compliant Deposit (FCD) Date
2019-08-16Usage metrics
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