A structure-guided molecular chaperone approach for restoring the transcriptional activity of the p53 cancer mutant Y220C
| Autor: | Andreas C. Joerger, Bradley Springett, Alan R. Fersht, Felix A. Dingler, Lorena Verduci, Matthias R. Bauer, Ketan J. Patel, Rhiannon N. Jones, John Spencer, Raysa Khan Tareque |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Transcriptional Activation
p53 Mutant Cancer therapy Carbazoles protein stabilization medicine.disease_cause DNA-binding protein 03 medical and health sciences 0302 clinical medicine Drug Discovery medicine Tumor Cells Cultured Humans RM0260 Cancer mutations 030304 developmental biology RM0300 Pharmacology 0303 health sciences Mutation Transcriptional activity Molecular Structure cancer mutations Chemistry molecular chaperones Cancer medicine.disease Cell biology 030220 oncology & carcinogenesis Molecular Medicine cancer therapy structure-based drug design Protein stabilization Tumor Suppressor Protein p53 Erratum tumor suppression CRISPR/Cas9 p53 knockout Research Article |
| Zdroj: | Future Medicinal Chemistry Future Med Chem |
| ISSN: | 1756-8919 |
| Popis: | Aim: The p53 cancer mutation Y220C creates a conformationally unstable protein with a unique elongated\ud surface crevice that can be targeted by molecular chaperones. We report the structure-guided optimization\ud of the carbazole-based stabilizer PK083. Materials & methods: Biophysical, cellular and x-ray\ud crystallographic techniques have been employed to elucidate the mode of action of the carbazole scaffolds.\ud Results: Targeting an unoccupied subsite of the surface crevice with heterocycle-substituted PK083\ud analogs resulted in a 70-fold affinity increase to single-digit micromolar levels, increased thermal stability\ud and decreased rate of aggregation of the mutant protein. PK9318, one of the most potent binders, restored\ud p53 signaling in the liver cancer cell line HUH-7 with homozygous Y220C mutation. Conclusion: The\ud p53-Y220C mutant is an excellent paradigm for the development of mutant p53 rescue drugs via protein\ud stabilization. Similar rescue strategies may be applicable to other cavity-creating p53 cancer mutations. |
| Databáze: | OpenAIRE |
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