BMN 673

Ферментативный ингибитор

This novel, orally bioavailable poly(ADP-ribose) polymerase, or PARP, inhibitor (FW = 380.35 g/mol; CAS 1207456-01-6), also known as (8S,9R)- 5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]phthalazin-3(7H)-one, targets PARP-mediated DNA repair (IC50 = 0.58 nM) of single-strand DNA breaks by the base-excision repair pathway. By enhancing the accumulation of DNA strand breaks, BMN 673 promotes genomic instability, eventually leading to apoptosis. BMN 673 exhibits selective anti-tumor cytotoxicity and elicits DNA repair biomarkers at much lower concentrations than earlier generation PARP1/2 inhibitors, including olaparib, rucaparib and veliparib. BMN 673 shows remarkable anti-tumor activity in vivo, with strong action against xenografted tumors carrying defects in DNA repair due to BRCA mutations or PTEN deficiency. Synergistic or additive anti-tumor effects are observed, when BMN 673 was combined with temozolomide, SN38 or platinum drugs.