Biological Activity
Talazoparib (BMN-673) 是一种高效的,具有口服活性的 PARP 1/2 抑制剂。Talazoparib 抑制 PARP1 和 PARP2 酶活性的 Ki 值分别为 1.2 nM 和 0.87 nM。Talazoparib 具有抗肿瘤活性。
Product Citations
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). |
 |
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). |
 |
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. |
 |
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). |
. figure s2..jpg) |
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 |
. figure 5..jpg) |
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. |
. figure 4..jpg) |
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) |
. figure 3..jpg) |
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. |
 |
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." |
 |
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." |
 |
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." |
-4.jpg) |
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. |
-3.jpg) |
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. |
-2.jpg) |
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. |
-1.jpg) |
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. |
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 Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
Chemical Information
Molecular Weight |
380.35 |
Formula |
C19H14F2N6O |
CAS Number |
1207456-01-6
|
Purity |
99.86% |
Solubility |
DMSO 30 mg/mL |
Storage |
at -20°C
|
References
[1] Yuqiao et al. Mol Cancer Ther. Structure and preclinical characterization of BMN 673, a potent and orally active PARP inhibitor as an anticancer agent.
[2] Ying et al. Mol Cancer Ther. Correlation of pharmacokinetics (PK), pharmacodynamics (PD) and in vivo antitumor activity of BMN 673 in preclinical models.