Design, synthesis, and activity evaluation of indole derivatives as potential stabilizers for p53 Y220C

The p53 Y220C mutation is frequently observed in human cancers. This mutation renders the p53 Y220C unstable at physiological temperatures, leading to a loss of its normal function and promoting tumor development. In this study, a total of eight compounds were designed and synthesized based on the active compound C8. The protein thermal shift assay revealed that both C8-3b and C8-6 exhibited similar activity of C8, with a ΔT_m value of +0.5 °C. Compounds C8-1a, C8-1b, and C8-2b were found to enhance the thermostability of p53 Y220C (ΔT_m: + 1.0 °C), the melting temperature exhibits an enhancement of 0.5 °C over the C8, indicating that these compounds possess the ability to stabilize p53 Y220C. The results of the cell viability assay revealed that C8-1b exhibited selective inhibitory effects on the proliferation of tumor cells harboring the p53 Y220C mutation. Furthermore, we utilized molecular docking and two-dimensional interaction analysis to elucidate the binding mode and key interactions of these compounds with p53 Y220C. Our study suggests that these compounds could potentially serve as lead compounds for enhancing the stability of p53 Y220C, thus providing a rational approach for designing small molecule stabilizers against p53 mutations.