Uses
BMN 673 is a pyrrolopyrazine derivative and anpoly (ADP-ribose) polymerase (PARP) inhibitor for patients with advanced or recurrent solid tumors such as ovarian and breast cancer.
Biological Activity
bmn673 is a potent and selective parp1/2 inhibitor with ki of 1.2 and 0.9 nm, respectively 1. it had no effect on panels of 72 receptors, ion channels, and enzymes 1. bmn673 showed ic50 value of 0.57 nm in enzymatic assay of parp1 1. in in vitro assay, it exhibited greater potency than other existing parp inhibitors, such as veliparib, rucaparib, and olaparib 2. it is also much more potent at trapping parp-dna complexes than other parp inhibitors 3.bmn673 has shown anti-tumor activity both in vitro and in vivo. it inhibited proliferation of tumor cells and xenografts with defects in homologous recombination 1. the combination of bmn673 and dna-damaging agents demonstrated synergistic anti-tumor effects 1. in addition, study showed that the expression levels of dna repair proteins and status of pi3k pathway predict response to bmn673 in small cell lung cancer 4.bmn673 is currently under investigation in multiple
Enzyme inhibitor
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.
References
1. shen y, rehman fl, feng y et al. bmn 673, a novel and highly potent parp1/2 inhibitor for the treatment of human cancers with dna repair deficiency. clin cancer res 2013; 19: 5003-5015.2. cardnell rj, byers la. proteomic markers of dna repair and pi3k pathway activation predict response to the parp inhibitor bmn 673 in small cell lung cancer--response. clin cancer res 2014; 20: 2237.3. murai j, huang sy, renaud a et al. stereospecific parp trapping by bmn 673 and comparison with olaparib and rucaparib. mol cancer ther 2014; 13: 433-443.4. cardnell rj, feng y, diao l et al. proteomic markers of dna repair and pi3k pathway activation predict response to the parp inhibitor bmn 673 in small cell lung cancer. clin cancer res 2013; 19: 6322-6328.
