Virtual screening, synthesis and activity evaluation of quinoline derivatives as potential stabilizers of p53 Y220C

p53 is widely regarded as the key regulator of anti-cancer mechanisms. The p53 Y220C mutation is one of the most common mutations. This mutation disrupts critical hydrogen bonds and the hydrophobic core in the DNA binding domain (DBD) of the p53 protein, creating a hydrophobic cavity and significantly reducing the stability of the protein structure. In this study, 31 derivatives were designed and synthesized from the emerging compound XFQ-8 obtained by virtual screening. Protein thermal shift assay analysis shows that XFQ-40, XFQ-42, XFQ-43, XFQ-50 and XFQ-20 have similar thermal shift activities with ΔT_m values about 6.5 ℃. XFQ-23 and XFQ-26 significantly improved the thermal stability of p53 Y220C (50 μM, ΔT_m =+7.5 ℃), and both XFQ-23 and XFQ-26 showed notable p53 reactivation activity, with EC₅₀ values of 99.46 μM and 78.98 μM respectively. The results demonstrate that these compounds hold promise as lead candidates for stabilizing mutant p53 Y220C, offering a rational strategy to develop small-molecule stabilizers against the p53 Y220C mutation. Virtual screening and SAR optimization identified quinolinone derivatives that stabilize p53 Y220C and restore its DNA-binding function.