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

Bauer, Matthias, Jones, Alice Rhiannon, Khan, Raysa, Springett, Bradley, Dingler, Felix, Verduci, Lorena, Patel, Ketan, Fersht, Alan, Joerger, Andreas and Spencer, John (2019) A structure-guided molecular chaperone approach for restoring the transcriptional activity of the p53 cancer mutant Y220C. Future Medicinal Chemistry, 11 (19). pp. 2491-2504. ISSN 1756-8919

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Abstract

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.

Item Type: Article
Schools and Departments: School of Life Sciences > Chemistry
Subjects: R Medicine > RM Therapeutics. Pharmacology > RM0260 Chemotherapy
R Medicine > RM Therapeutics. Pharmacology > RM0300 Drugs and their actions
Depositing User: John Spencer
Date Deposited: 19 Aug 2019 11:27
Last Modified: 01 Nov 2019 14:00
URI: http://sro.sussex.ac.uk/id/eprint/85534

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Project NameSussex Project NumberFunderFunder Ref
Rescuing p53 Function in Cancer. Targeting the Y220C MutationG2344WORLDWIDE CANCER RESEARCH18-0043