Small molecules that targeting p53 Y220C protein: mechanisms, structures, and clinical advances in anti-tumor therapy

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• The p53 protein, known as the "Guardian of the Genome," is frequently mutated in over half of all malignant tumors.
• Mutant p53 promotes tumor progression and metastasis, making it a critical target for cancer therapy.
• Targeting mutant p53 is challenging due to the absence of typical small molecule binding pockets.

Purpose of the Study:

• To elucidate the role of mutant p53 Y220C in tumorigenesis and its related signaling pathways.
• To review therapeutic strategies targeting mutant p53 Y220C.
• To discuss clinical progress and hurdles in developing p53 Y220C-targeted cancer therapies.

Main Methods:

• Detailed review of p53 signaling pathways and the mechanism of p53 Y220C in cancer.
• Analysis of two classes of p53 Y220C modulators: conformation restorers and histone acetyltransferase recruiters.
• Examination of clinical trial data and therapeutic challenges.

Main Results:

• Mutant p53 Y220C forms a unique cavity suitable for small molecule drug design.
• Modulators can restore wild-type p53 conformation or recruit p300/CBP for p53 Y220C acetylation.
• Acetylation by p300/CBP leads to apoptosis gene upregulation and DNA damage response pathway downregulation.

Conclusions:

• Targeting the p53 Y220C mutation presents a viable therapeutic avenue in oncology.
• Developing small molecules to exploit the p53 Y220C binding site offers a promising strategy.
• Further clinical development is necessary to overcome challenges in p53 Y220C-mediated tumor therapy.