Synthesis, molecular modeling, and biological evaluation of novel RAD51 inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• RAD51 recombinase is crucial for cancer cell survival and proliferation.
• Targeting RAD51 is a promising strategy for difficult-to-treat and therapy-resistant cancers, such as triple-negative breast cancer.
• Existing therapeutics often show limited efficacy against these aggressive cancer types.

Purpose of the Study:

• To design, synthesize, and evaluate novel small molecule inhibitors of RAD51.
• To identify potent RAD51 inhibitors with potential therapeutic applications in oncology.
• To assess the efficacy and mechanism of action of these novel compounds against various cancer cell types.

Main Methods:

• Synthesis and chemical evaluation of a panel of RAD51 inhibitors (IBR compounds).
• Assessment of growth inhibition activity in human cancer cell lines, including MBA-MD-468 (triple-negative breast cancer).
• Evaluation of compound effects on RAD51 multimerization, homologous recombination repair, and induction of apoptotic cell death.

Main Results:

• Identified IBR120 as a novel small molecule RAD51 inhibitor with significantly improved growth inhibition activity (4.8-fold) in triple-negative breast cancer cells.
• IBR120 demonstrated broad-spectrum inhibition of proliferation across various cancer cell types.
• Observed a 10-fold difference in IC50 values between normal and cancer cells, indicating selectivity.
• IBR120 disrupted RAD51 multimerization, impaired homologous recombination repair, and induced apoptosis.

Conclusions:

• Novel RAD51 inhibitors, particularly IBR120, show significant potential as therapeutic agents.
• IBR120's ability to inhibit cancer cell proliferation and induce apoptosis makes it a strong candidate for pharmaceutical development.
• These findings support the development of RAD51-targeted therapies for challenging cancers.