Distinct novel quinazolinone exhibits selective inhibition in MGC-803 cancer cells by dictating mutant p53 function

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Mutant p53 proteins are frequently found in cancer cells and contribute to tumor development.
• Targeting mutant p53 offers a potential strategy for cancer therapy.
• Novel chemical compounds are being investigated for their ability to modulate mutant p53 activity.

Purpose of the Study:

• To investigate the anti-cancer effects of novel quinazolinone derivatives on p53 mutant cancer cells.
• To identify potent compounds that selectively target and inhibit mutant p53 cancer cells.
• To elucidate the molecular mechanisms underlying the anti-cancer activity of the most effective compounds.

Main Methods:

• Synthesis and screening of a series of quinazolinone derivatives (compounds 4-8 a-i).
• Evaluation of anti-cancer activity in various p53 mutant and wild-type cancer cell lines, including A375 and WI-38 cells.
• Cell cycle analysis (S/G2 phase arrest) and assessment of cell size reduction.
• Molecular mechanism studies involving p53 phosphorylation and acetylation, Cdk2 deregulation, and Bim-mediated apoptosis.

Main Results:

• Compound 4a demonstrated broad-spectrum anti-cancer effects.
• Compound 6c exhibited selective inhibition of p53 mutant cancer cells with low toxicity to wild-type cells and normal fibroblasts.
• Compound 6c induced S/G2 phase arrest, reduced cell size, and triggered apoptosis by targeting mutant p53 function.
• Molecular studies revealed that 6c acts as a dual-targeting inhibitor of p53 phosphorylation and acetylation, leading to Cdk2 deregulation and Bim-mediated apoptosis.

Conclusions:

• Novel quinazolinone derivative 6c selectively targets and inhibits p53 mutant cancer cells.
• Compound 6c utilizes a unique mechanism involving p53 modulation, cell cycle arrest, and apoptosis induction.
• 6c represents a promising therapeutic agent for cancers harboring mutant p53, with potential for targeted cancer therapy.