The novel curcumin analogue AKT-100 targets mutant p53 in gynecologic cancer cells

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Loss of p53 tumor suppressive functions is prevalent in advanced cancers, often due to TP53 mutations.
• Mutant p53 proteins can gain oncogenic functions, losing wild-type tumor suppressor roles.
• Targeting mutant p53 directly offers potential advantages over targeting downstream pathways.

Purpose of the Study:

• To develop novel molecules targeting missense mutant p53.
• To identify and characterize a potent curcumin analogue for mutant p53 reactivation.
• To evaluate the therapeutic potential of AKT-100 in cancer treatment.

Main Methods:

• Development of novel curcumin-derived molecules.
• Identification and testing of the active analogue AKT-100.
• Assessment of AKT-100's binding to mutant p53 and functional restoration.
• Evaluation of AKT-100's efficacy in ovarian and endometrial cancer cells.
• RNA sequencing to confirm gene expression changes.
• Synergistic studies with olaparib and chemotherapy.

Main Results:

• A novel curcumin analogue, AKT-100, was identified.
• AKT-100 binds to mutant p53 and reinstates wild-type p53 functionality.
• AKT-100 demonstrated potent cell killing in ovarian and endometrial cancer cells (100-300 nM).
• AKT-100 showed synergy with olaparib and chemotherapy by inhibiting alternative DNA repair.
• RNA sequencing confirmed reactivation of p53-driven genes (e.g., CDKN1A, GADD45A, PMAIP1, DR5) and inhibition of DNA replication/repair.

Conclusions:

• AKT-100 is a promising p53 reactivator that directly targets missense mutant p53.
• This agent holds potential as a novel therapeutic for cancers with gain-of-function mutant p53.
• AKT-100's ability to restore p53 function and synergize with existing treatments warrants further investigation.