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BMN673

Cat. No. M1732
BMN673 Structure
Synonym:

BMN-673, LT-673,Talazoparib

Size Price Availability Quantity
10mg USD 245 In stock
50mg USD 650 In stock
100mg USD 1000 In stock
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Quality Control
Biological Activity

BMN673 is an orally bioavailable inhibitor of the nuclear enzyme poly (ADP-ribose) polymerase (PARP) with potential antineoplastic activity. PARP inhibitor BMN-673 selectively binds to PARP and prevents PARP-mediated DNA repair of single strand DNA breaks via the base-excision repair pathway. BMN-673 has been proven to be highly active in mouse models of human cancer and also appears to be more selectively cytotoxic with a longer half-life and better bioavailability as compared to other compounds in development. BMN 673 selectively kills cancer cells with BRCA-1 or BRCA-2 mutations. Oral dosing of BMN 673 results in complete regression of the BRCA-deficient tumors in xenograft tumor model studies. In addition, we found that tumor cells with PTEN mutation are highly sensitive to BMN 673 treatment in vitro. Xenograft tumor models that harbor PTEN deficiency responded to oral BMN 673 treatment with significant tumor growth delay. Currently, BMN 673 is in phase 1 clinical trials with solid tumors or hematological malignancies.

Protocol
Cell Experiment
Cell lines Capan-1 and MIA PaCa-2
Preparation method Real-time cell analysis (xCELLigence)
Concentrations
Incubation time 48 h
Animal Experiment
Animal models Patient-derived xenograft (PDX) model
Formulation Solubilized in DMSO and diluted with PBS containing 10% dimethylacetamide (Sigma-Aldrich) and 6% Solutol (Sigma-Aldrich).
Dosages 0.33 mg/kg, 0.05 cc, once daily
Administration oral gavage
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information
Molecular Weight 380.35
Formula C19H14F2N6O
CAS Number 1207456-01-6
Purity 99.77%
Solubility DMSO
Storage at -20°C
Customer Product Validations & Biological Datas
Source Cancer Cell (2016). Figure 4. BMN 673 (Abmole Bioscience)
Method
Cell Lines TNBC cells
Concentrations 1–5 nM
Incubation Time 72 h
Results As expected, TNBC cells mutant for BRCA1 (SUM149PT) are sensitive to talazoparib (10 nM BMN 673) alone, but these cells are even more sensitive to a combination of talazoparib (1 and 10 nM) and AZA (150 nM).
Rating
Source Cancer Cell (2016). Figure 3. BMN 673 (Abmole Bioscience)
Method MTS assay
Cell Lines MDA-MB-231 cells, MOLM14 cells
Concentrations 2.5–20 nM
Incubation Time 72 h
Results Significant decrease in survival was also observed with combination drug treatments (AZA and BMN 673 or DAC and BMN 673) compared with either drug alone (Figures 3A–3D, middle and lower panels).
Rating
Source Cancer Cell (2016). Figure 2. BMN 673 (Abmole Bioscience)
Method
Cell Lines MDA-MB-231 cells, MOLM14 cells
Concentrations 10 nM
Incubation Time 72 h
Results Also, in MOLM14 AML cells, combination dosing with DAC (5 nM) and BMN 673 (5 nM) induces increases in gH2AX foci, as compared with single-drug treatments (Figure 2G). In a key association with the above data, both MOLM14 AML and MDA-MB-231 TNBC cells treated with the combination of the two drugs exhibit synergistic cytotoxicity, as assessed by the CalcuSyn model.
Rating
Source Cancer Cell (2016). Figure 1. BMN 673 (Abmole Bioscience)
Method
Cell Lines MOLM14 cells
Concentrations 1, 2.5, and 5 nM
Incubation Time 72 h
Results In our present study, talazoparib (BMN 673) at very low nanomolar concentrations (1, 2.5, or 5 nM) also traps PARP1 in chromatin extracts (Figure 1C) to thesame extent as the weaker PARPi ABT888 at much higher concentrations (500 nM) (Figure S2A).
Rating
Source McGill University (2015). Figure S2.BMN 673 (Abmole Biosciences, Hong Kong, China).
Method Cells were plated in 6-well plates at 2x104 cells/well and treated 24 h later with veliparib, cisplatin or BMN 673.
Cell Lines Capan-1 (HTB-79), MIA PaCa-2 (CRL-1420) and PANC-1 (CRL-1469)
Concentrations
Incubation Time 24 h
Results The cytotoxicity fold-differences and IC50 values of cisplatin and BMN 673 appeared comparable, suggesting that the efficacy of cisplatin and BMN 673 may be similar and that BMN 673 may be a less toxic alternative to cisplatin21,22
Rating
Source McGill University (2015). Figure 5.BMN 673 (Abmole Biosciences, Hong Kong, China).
Method Cells were plated in 6-well plates at 2x104 cells/well and treated 24 h later with veliparib, cisplatin or BMN 673.
Cell Lines Capan-1 (HTB-79), MIA PaCa-2 (CRL-1420) and PANC-1 (CRL-1469)
Concentrations
Incubation Time 24 h
Results These data suggest that the GI effects observed in the cisplatin and BMN 673 treatment arms are due to the anti-proliferative effects of these agents, and that these two drugs have equivalent anti-proliferative effects on a PDAC arising from germline BRCA2 mutation carriers.
Rating
Source McGill University (2015). Figure 4.BMN 673 (Abmole Biosciences, Hong Kong, China).
Method Cisplatin and BMN 673 were solubilized in DMSO and diluted with PBS containing 10% dimethylacetamide and 6% Solutol.
Cell Lines Capan-1 (HTB-79), MIA PaCa-2 (CRL-1420) and PANC-1 (CRL-1469)
Concentrations 0.33 mg/kg,
Incubation Time
Results Figure 4A demonstrates marked growth inhibition with cisplatin and BMN 673 treatments. End-point tumor volumes correlated with the growth curve observations.In support of our in vitro findings, treatment with BMN 673 (10 tumors) also resulted in significant GI compared with vehicle-treated controls (8 tumors)
Rating
Source McGill University (2015). Figure 3.BMN 673 (Abmole Biosciences, Hong Kong, China).
Method Cisplatin and BMN 673 were solubilized in DMSO and diluted with PBS containing 10% dimethylacetamide and 6% Solutol.
Cell Lines Capan-1 (HTB-79), MIA PaCa-2 (CRL-1420) and PANC-1 (CRL-1469)
Concentrations 0.33 mg/kg,
Incubation Time
Results This provided us with additional cell lines harboring intermediate HDR activity with which to further characterize the in vitro effectiveness of BMN 673 compared to veliparib and cisplatin prior to undertaking a BMN 673 preclinical PDX trial.
Rating
Source Cell Reports (2015). Figure 4. BMN-673 was purchased from Abmole (BMN673, 1207456-01-6)
Method Orthotopic EWS Xenograft Model
Cell Lines EWS cell lines
Concentrations 0.1 mg/kg
Incubation Time 12–18 weeks
Results "The following percentages of each group showed CR: 15% (3/20) in the veliparib + IRN + TMZ (50%) group, 71% (12/17) in the olaparib + IRN + TMZ (50%) group, and 88% (14/16) in the BMN-673 (80%) + IRN + TMZ (30%) group. The Xenogen data correlated with tumor burden and histopathology."
Rating
Source Cell Reports (2015). Figure 4. BMN-673 was purchased from Abmole (BMN673, 1207456-01-6)
Method Orthotopic EWS Xenograft Model
Cell Lines EWS cell lines
Concentrations 0.1 mg/kg
Incubation Time 12–18 weeks
Results "The tolerability of TMZ was even less in combination with BMN-673.The BMN- 673 (80%) + IRN + TMZ (30%) group had four mice with CR."
Rating
Source Cell Reports (2015). Figure 2. BMN-673 was purchased from Abmole (BMN673, 1207456-01-6)
Method Cell Titer Glo (Promega, G7570)
Cell Lines EW8, ES6, SAOS2 cell lines
Concentrations 0, 1, 2.5, 5, 10, 20, 50, or 100 µM
Incubation Time 72hr or 144hr
Results "At 72 hr of exposure, EW-8, ES-8, and ES-1 cells were sensitive to BMN-673 and olaparib, and, at 144 hr, all EWS cell lines except ES-6 were sensitive to all three PARPis."
Rating
Source Cancer Letters(2015). Figure 5. BMN 673 (Abmole Biosciences, Hong Kong, China)
Method Immunohistochemistry H&E staining
Cell Lines
Concentrations
Incubation Time
Results The GI effects observed in the cisplatin and BMN 673 treatment arms are due to both anti-proliferative and proapoptotic effects of these agents on a PDAC arising from germline BRCA2 mutation carriers.
Rating
Source Cancer Letters(2015). Figure 4. BMN 673 (Abmole Biosciences, Hong Kong, China)
Method Preclinical PDX trial
Cell Lines
Concentrations 0.33 mg/kg, 0.05 cc, once daily
Incubation Time 70 days
Results Treatment with BMN 673 (10 tumors) also resulted in significant GI compared with vehicle treated controls (8 tumors) (195.05 mm3 ± 95.21 mm3 (SD) versus 520.55 mm3 ± 62.68 mm3 (SD); p = 0.0006); cisplatin and BMN 673 have similar efficacies in this BRCA2 associated PDAC.
Rating
Source Cancer Letters(2015). Figure 4. BMN 673 (Abmole Biosciences, Hong Kong, China)
Method long-term colony formation assays
Cell Lines PANC-1 BRCA2-knockdown cell lines
Concentrations 0.3125; 0.625; 1.25; 2.5; 5μM
Incubation Time 10 days
Results The IC50 values with BMN 673 were 0.57 μM ± 0.16 μM (p < 0.0001) and 0.53 μM ± 0.13 μM(p < 0.0001) in the PANC-1_shRNA 2 [BRCA2] and PANC-1_shRNA 3 [BRCA2] cell lines compared to 1.22 μM ± 0.25 μM in the control cell line. BMN 673 is a more effective PARPi for BRCA2-associated PDAC compared to the earlier-generation PARPis such as veliparib, and that BMN 673, rather than veliparib, should be selected for our preclinical PDX trial evaluation.
Rating
Source Cancer Letters(2015). Figure 2. BMN 673 (Abmole Biosciences, Hong Kong, China)
Method Real-time cell analysis (xCELLigence)
Cell Lines Capan-1 and MIA PaCa-2
Concentrations unnoted
Incubation Time 48 hours
Results Mean IC50 values were 11.4 mM ± 1.4 mM versus 12.7 mM ± 3.6 mM for gemcitabine (NS), 38.3 μM ± 7.3 μM versus 10.2 ± 1.5 μM (p = 0.0150) for cisplatin, and 58.23 ± 8.1 μM versus 16.0 ± 5.4 μM (p = 0.0105) for BMN 673 in MIA PaCa-2 versus Capan-1 cells, respectively. The efficacy of cisplatin and BMN 673 may be similar and that BMN 673 may be a less toxic alternative to cisplatin.
Rating
Product Citations
References

Structure and preclinical characterization of BMN 673, a potent and orally active PARP inhibitor as an anticancer agent.
Yuqiao et al. Mol Cancer Ther. 2011 Nov;10(11 Suppl).

Correlation of pharmacokinetics (PK), pharmacodynamics (PD) and in vivo antitumor activity of BMN 673 in preclinical models.
Ying et al. Mol Cancer Ther. 2011 Nov;10(11 Suppl).

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BMN673 isomer

BMN-673 8R,9S

BMN-673 (8R,9S) is the (8R,9S) enantiomer of BMN-673.BMN673 is a potent inhibitor of poly (ADP-ribose) polymerases (PARP)-1 and -2.

  Catalog
Abmole Inhibitor Catalog 2017




Keywords: BMN673, BMN-673, LT-673,Talazoparib supplier, PARP, inhibitors

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