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A structure-guided molecular chaperone approach for restoring the transcriptional activity of the p53 cancer mutant Y220C

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Version 2 2023-06-07, 08:27
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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 Spencer
Aim: 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 Chemistry

ISSN

1756-8919

Publisher

Future Science

Issue

19

Volume

11

Page range

2491-2504

Department affiliated with

  • Chemistry Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2019-08-19

First Open Access (FOA) Date

2019-11-01

First Compliant Deposit (FCD) Date

2019-08-16

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