Targeting protein-protein interactions in the DNA damage response pathways for cancer chemotherapy

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Cellular DNA damage response (DDR) is crucial for maintaining genomic stability.
• Altered DDR pathways are a hallmark of cancer, creating dependencies that can be exploited therapeutically.
• Traditional cancer therapies often target enzyme active sites, limiting the scope of druggable targets within the DDR.

Purpose of the Study:

• To review the emerging strategy of targeting protein-protein interactions (PPIs) within the DDR network for cancer therapeutics.
• To discuss structure-based design of small molecule PPI inhibitors.
• To identify novel PPI targets for anti-cancer drug development.

Main Methods:

• Review of existing literature on DDR pathways and PPIs.
• Analysis of structure-based drug design principles for PPI inhibitors.
• Summary of current small molecule inhibitors targeting DDR PPIs.

Main Results:

• DDR alterations create dependencies in cancer cells, making them vulnerable to targeted therapies.
• Small molecule inhibitors of DDR PPIs can selectively kill cancer cells or sensitize them to genotoxic therapies.
• Several DDR pathways, including DNA damage sensing, repair, and tolerance, harbor potential PPI targets.

Conclusions:

• Targeting DDR-associated PPIs represents a promising avenue for developing novel anti-cancer drugs.
• Structure-based design of small molecule PPI inhibitors offers a viable strategy to overcome limitations of traditional drug discovery.
• Further exploration of DDR PPIs may yield new chemotherapeutic agents with improved efficacy and selectivity.