1207456-01-6 Usage
Description
BMN 673, also known as Talazoparib, is a novel PARP (Poly (ADP-ribose) polymerase) inhibitor with an IC50 of 0.58 nM in a cell-free assay. It is a potent inhibitor of PARP-2 and is highly sensitive to PTEN mutation. However, it does not inhibit PARG (Poly (ADP-ribose) glycohydrolase). Talazoparib is currently in Phase 3 of clinical development.
Uses
Used in Oncology:
BMN 673 is used as an anticancer agent for the treatment of various types of cancer. Its high sensitivity to PTEN mutation makes it a promising candidate for the treatment of cancers with PTEN deficiency.
Used in Drug Development:
BMN 673 is used as a research tool in the development of new drugs targeting PARP enzymes. Its potent inhibitory activity against PARP-2 and its selectivity for PARP enzymes make it a valuable compound for studying the role of PARP enzymes in various diseases, including cancer.
Used in Biochemical Research:
BMN 673 is used as a biochemical research tool for studying the function and regulation of PARP enzymes. Its high potency and selectivity for PARP-2 make it an ideal compound for investigating the role of PARP-2 in various biological processes.
Used in Diagnostics:
BMN 673 can be used as a diagnostic tool for identifying patients with PTEN mutations, as it is highly sensitive to this mutation. This can help in the development of personalized treatment plans for patients with PTEN-deficient cancers.
Features
Most potent and selective PARPi reported thus far.
In vitro
BMN-673 selectively binds to PARP and prevents PARP-mediated DNA repair of single strand DNA breaks via the base-excision repair pathway. This enhances the accumulation of DNA strand breaks, promotes genomic instability and eventually leads to apoptosis. BMN 673 selectively kills cancer cells with BRCA-1 or BRCA-2 mutations. BMN 673 demonstrates single-agent cytotoxicityin BRCA-1 mutant (MX-1, IC50 = 0.3 nM) and BRCA-2 mutant cells (Capan-1, IC50 = 5 nM). In contrast, in MRC-5 normal human fibroblastand other tumor cell lines with wild-type BRCA-1 and BRCA-2 genes, IC50 of BMN 673 ranges between 90 nM and 1.9 μM. In cultured human cancer cells, BMN 673 also significantly enhances the cytotoxic efficacy of both Temozolomide and SN-38. Off-target molecular screening did not identify significant non-specific activity for this class of PARP inhibitors.
In vivo
In rat pharmacokinetic studies, BMN 673 displays >50% oralbioavailability and pharmacokinetic properties that enable singledaily dosing. In MX-1 xenograft tumor model studies, daily oral dosingof BMN 673 significantly enhances the antitumor effects ofcytotoxic therapies in a dose-dependent manner.
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.
Check Digit Verification of cas no
The CAS Registry Mumber 1207456-01-6 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,2,0,7,4,5 and 6 respectively; the second part has 2 digits, 0 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 1207456-01:
(9*1)+(8*2)+(7*0)+(6*7)+(5*4)+(4*5)+(3*6)+(2*0)+(1*1)=126
126 % 10 = 6
So 1207456-01-6 is a valid CAS Registry Number.
1207456-01-6Relevant articles and documents
COMPOUNDS, COMPOSITIONS, AND METHODS FOR TREATMENT OF DISEASES INVOLVING ACIDIC OR HYPOXIC DISEASED TISSUES
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Page/Page column 136; 137, (2019/07/20)
Compounds for treatment of diseases having acidic or hypoxic diseased tissues and pharmaceutical compositions comprising the compounds, as well as methods for making and using the compounds and compositions.
DIHYDROPYRIDOPHTHALAZINONE INHIBITORS OF POLY (ADP-RIBOSE) POLYMERASE (PARP) FOR THE TREATMENT OF MULTIPLE MYELOMA
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, (2013/03/26)
Provided is a methods of treating multiple myeloma with inhibitors of poly(ADP-ribose)polymerase according to Formula (I):
PROCESSES OF SYNTHESIZING DIHYDROPYRIDOPHTHALAZINONE DERIVATIVES
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, (2011/08/22)
Provided herein are processes for synthesizing dihydropyridophthalazinone derivatives, such as for example, 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 and its stereoisomers, which are potent poly(ADP-ribose)polymerase (PARP) inhibitors as well as novel synthetic intermediate compounds.
