The discovery of nongenotoxic activators of p53: building on a cell-based high-throughput screen

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Reactivating mutant p53 or non-genotoxically increasing p53 levels are major challenges in anti-cancer drug discovery.
• Recent advancements indicate these goals are becoming achievable.
• Endogenous p53 activators are crucial for developing effective cancer therapeutics.

Purpose of the Study:

• To review the application of cell-based high-throughput screening (HTS) for identifying novel non-genotoxic p53 activators.
• To highlight the importance of cell-based screening in early-phase drug discovery for therapeutic relevance.
• To discuss the feasibility of target identification for compounds identified through this screening approach.

Main Methods:

• Focuses on cell-based high-throughput screening (HTS) methodologies.
• Reviews strategies for discovering compounds that activate endogenous p53 in a non-genotoxic manner.
• Discusses the process and challenges of protein target identification for identified compounds.

Main Results:

• Cell-based HTS is a viable strategy for discovering novel non-genotoxic p53 activators.
• Compounds identified through cell-based screening show promise for direct therapeutic development.
• Protein target identification for p53-activating compounds, while challenging, is achievable.

Conclusions:

• Cell-based HTS is a powerful tool for advancing anti-cancer drug discovery by targeting p53.
• The identification of non-genotoxic p53 activators is a critical step towards new cancer therapies.
• Overcoming the challenge of target identification strengthens the utility of cell-based screening in drug development.