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

Vladimir Burmistrov, Rahul Saxena, Dmitry Pitushkin, Gennady M Butov, Fung-Lung Chung, Monika Aggarwal

Journal of medicinal chemistry 2021 May 27

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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.

Citation

Vladimir Burmistrov, Rahul Saxena, Dmitry Pitushkin, Gennady M Butov, Fung-Lung Chung, Monika Aggarwal. Adamantyl Isothiocyanates as Mutant p53 Rescuing Agents and Their Structure-Activity Relationships. Journal of medicinal chemistry. 2021 May 27;64(10):6621-6633