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

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. Results: Targeting an unoccupied subsite of the surface crevice with heterocycle-substituted PK083 analogues 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.