Quinazolinone derivatives as inhibitors of homologous recombinase RAD51

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• RAD51 is crucial for homologous recombination DNA repair.
• RAD51 overexpression is linked to drug-resistant cancers, particularly triple-negative breast cancer (TNBC).
• Targeting RAD51 offers a strategy to enhance cancer therapy efficacy.

Purpose of the Study:

• To explore structure-activity relationships of quinazolinone derivatives as RAD51 inhibitors.
• To identify novel small molecules that inhibit RAD51 function.
• To evaluate the potential of RAD51 inhibition in sensitizing TNBC cells to DNA-damaging agents.

Main Methods:

• Synthesis and evaluation of a library of quinazolinone derivatives.
• Assessing cell growth inhibition in TNBC cell lines.
• Measuring inhibition of RAD51 foci formation after irradiation.
• Evaluating the effect of compounds on TNBC cell sensitivity to DNA damage.

Main Results:

• A novel quinazolinone derivative, compound 17, was identified as a potent RAD51 inhibitor.
• Compound 17 demonstrated up to 15-fold greater inhibition of TNBC cell growth compared to compound B02.
• Compound 17 showed approximately 2-fold increased inhibition of irradiation-induced RAD51 foci.
• Compound 17 significantly reduced TNBC cell resistance to DNA damage.

Conclusions:

• Quinazolinone derivatives represent a promising class of small molecule inhibitors targeting RAD51.
• Compound 17 is a potent inhibitor of RAD51 and enhances the sensitivity of TNBC cells to DNA-damaging therapies.
• Targeting RAD51 with novel inhibitors like compound 17 holds potential for developing new therapeutic strategies for aggressive TNBC.