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© 2021 American Chemical Society.Mutant p53 rescue by small molecules is a promising therapeutic strategy. In this structure–activity relationship study, we examined a series of adamantyl isothiocyanates (Ad–ITCs) to discover novel agents as therapeutics by targeting mutant p53. We demonstrated that the alkyl chain connecting adamantane and ITC is a crucial determinant for Ad–ITC inhibitory potency. Ad–ITC 6 with the longest chain between ITC and adamantane displayed the maximum growth inhibition in p53R280K, p53R273H, or p53R306Stop mutant cells. Ad–ITC 6 acted in a mutant p53–dependent manner. It rescued p53R280K and p53R273H mutants, thereby resulting in upregulating canonical wild–type (WT) p53 targets and phosphorylating ATM. Ad–ISeC 14 with selenium showed a significantly enhanced inhibitory potency, without affecting its ability to rescue mutant p53. Ad–ITCs selectively depleted mutant p53, but not the WT, and this activity correlates with their inhibitory potencies. These data suggest that Ad–ITCs may serve as novel promising leads for the p53–targeted drug development.
