RI-1

RI-1 is a first-in-class small molecule inhibitor of the RAD51 recombinase, a key protein in the homologous recombination (HR) DNA damage repair pathway. It functions by covalently binding to the Cys319 residue on the surface of the RAD51 protein, which disrupts the protein-protein interactions at the subunit interface necessary for the formation of the active RAD51 nucleoprotein filament on single-stranded DNA. By blocking the HR pathway, RI-1 effectively impairs the repair of DNA double-strand breaks, thereby sensitizing cancer cells to DNA-damaging treatments such as ionizing radiation and cross-linking chemotherapeutic agents. While primarily used as a chemical tool in preclinical research, RI-1 has also served as a structural foundation for the development of next-generation RAD51-targeting therapies, including proteolysis-targeting chimeras (PROTACs).