Adamantyl Isothiocyanates as Mutant p53 Rescuing Agents and Their Structure–Activity Relationships

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.