RI-1

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Background

RI-1 Description:IC50: 5~30 μM [1]RAD51 is a eukaryote gene, encoding RAD51 protein that participates in DNA damage induction and complex signal pathway of cell cycle checkpoint of homologous recombination in cells. RI-1 inhibits the over-expression of RAD51 in cancer cells by bonding covalently to the surface of RAD51 protein at Cys 319 and irreversibly loosen a protein-protein interface that is essential for filament formation and recombinase activity.In vitro: RI-1 binds covalently to the surface of RAD51 protein at cysteine 319 that likely destabilizes an interface used by RAD51 monomers to oligomerize into filaments on DNA. Correspondingly, the molecule inhibits the formation of subnuclear RAD51 foci in cells following DNA damage, while leaving replication protein A focus formation unaffected. Finally, it potentiates the lethal effects of a DNA cross-linking drug in human cells. Given that this inhibitory activity is seen in multiple human tumor cell lines, RI-1 holds promise as an oncologic drug [1]. In vivo: There are limits to the development of RI-1 in pre-clinical in vivo models due to its short half-life in tissue culture media and aqueous buffers. RI-2, a homolog of RI-1, was created that mitigated these effects(119). RI-2 was shown to bind Rad51 and inhibit the nuclear foci of Rad51 at sites of DNA damage. RI-2 is currently the subject of further in vitro and in vivo studies and is being used to identify third generation analogs that inhibit the function of Rad51 [2]. Clinical trial: Up to now, RI-1 is still in the preclinical development stage.

[1] Budke B, Logan HL, Kalin JH, Zelivianskaia AS, Cameron McGuire W, Miller LL, Stark JM, Kozikowski AP, Bishop DK, Connell PP. RI-1: a chemical inhibitor of RAD51 that disrupts homologous recombination in human cells. Nucleic Acids Res. 2012;40(15):7347-57.
[2] Christian Jekimovs, Emma Bolderson, Amila Suraweera, Mark Adams, Kenneth J. O’Byrne, and Derek J. Richard. Chemotherapeutic Compounds Targeting the DNA Double-Strand Break Repair Pathways: The Good, the Bad, and the Promising. Front Oncol. 2014; 4: 86.