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

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Oncology

Background:

• Mutant p53 proteins are frequently found in human cancers and often lose their tumor-suppressive functions.
• Restoring wild-type p53 activity through small molecules is a potential therapeutic strategy for cancer treatment.

Purpose of the Study:

• To explore adamantyl isothiocyanates (Ad-ITCs) as novel therapeutics targeting mutant p53.
• To investigate the structure-activity relationships of Ad-ITCs for optimizing their inhibitory and mutant p53-rescuing potential.

Main Methods:

• Synthesis and evaluation of a series of adamantyl isothiocyanates (Ad-ITCs).
• Assessing the inhibitory effects of Ad-ITCs on the growth of cancer cells with specific p53 mutations (p53^R280K, p53^R273H, p53^R306Stop).
• Investigating the mechanism of action, including mutant p53 rescue, upregulation of wild-type p53 targets, and ATM phosphorylation.

Main Results:

• The alkyl chain length connecting adamantane and the isothiocyanate group is critical for inhibitory potency.
• Ad-ITC 6, with the longest alkyl chain, demonstrated maximum growth inhibition in mutant p53 cancer cells.
• Ad-ITC 6 rescued p53^R280K and p53^R273H mutants, leading to the upregulation of wild-type p53 targets and ATM phosphorylation.
• Ad-ISeC 14, containing selenium, showed enhanced potency without compromising mutant p53 rescue.
• Ad-ITCs selectively depleted mutant p53, with potency correlating to depletion levels.

Conclusions:

• Ad-ITCs are effective in inhibiting the growth of cancer cells harboring specific p53 mutations.
• The structure of Ad-ITCs, particularly the linker length, can be optimized for enhanced therapeutic efficacy.
• Ad-ITCs represent promising lead compounds for developing novel p53-targeted cancer therapies.