Talazoparib (BMN-673) is a highly potent, orally active PARP1/2 inhibitor.Talazoparib inhibits PARP1 and PARP2 enzyme activity with Kis of 1.2 nM and 0.87 nM, respectively. Talazoparib shows EC50s of 0.3 nM, 5 nM and 0.31 for MX-1 cells (BRCA1 mutant), Capan-1 cells (BRCA2 mutant) and MRC-5 cells (normal).
In vivo, Talazoparib (0.33 mg/kg; i.g.; once daily; for 28 days) exhibits antitumor activity against BRCA1 mutant breast cancer model in mice
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.
Application
long-term colony formation assays
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.
Application
Preclinical PDX trial
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.
Application
Immunohistochemistry H&E staining
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.
Application
Cell Titer Glo (Promega, G7570)
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."
Application
Orthotopic EWS Xenograft Model
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."
Application
Orthotopic EWS Xenograft Model
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."
Application
Cisplatin and BMN 673 were solubilized in DMSO and diluted with PBS containing 10% dimethylacetamide and 6% Solutol.
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.
Application
Cisplatin and BMN 673 were solubilized in DMSO and diluted with PBS containing 10% dimethylacetamide and 6% Solutol.
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)
Application
Cells were plated in 6-well plates at 2x104 cells/well and treated 24 h later with veliparib, cisplatin or BMN 673.
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.
Application
Cells were plated in 6-well plates at 2x104 cells/well and treated 24 h later with veliparib, cisplatin or BMN 673.
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
Application
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).
Application
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.
Application
MTS assay
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).
Application
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).
Protocol (for reference only)
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
Chemical Information
Molecular Weight
380.35
Formula
C19H14F2N6O
CAS Number
1207456-01-6
Solubility (25°C)
DMSO 25 mg/mL
Storage
Powder -20°C 3 years ; 4°C 2 years
In solvent -80°C 6 months ; -20°C 1 month
AZD 2281 (Olaparib, KU-0059436) is a potent PARP (poly ADP-ribose polymerase) inhibitorwith IC50 of 5 and 1 nM for PARP-1and PARP-2 respectively. Olaparib is an autophagy and mitophagy activator.
3-Aminobenzamide (PARP-IN-1) is a novel poly(ADP-ribose) polymerase (PARP) inhibitor, and it inhibits cell apoptosis after SCI (Spinal Cord Injury) in caspase-independent way.
MK-4827 (Niraparib) is a selective PARP1/2 inhibitor with an IC50 value of 3.8 nM/2.1 nM that increases the formation of PARP-DNA complexes through inhibition of PARPase activity, leading to DNA damage, apoptosis, PARP-1-dependent cell death (parthanatos) and cell death. Strong effector activity when acting on cancer cells harboring mutant BRCA-1 and BRCA-2. It is more than 330-fold more selective than PARP3, V-PARP and Tank1.
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