BMN673 (Talazoparib)

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 K_i 值分别为 1.2 nM 和 0.87 nM。Talazoparib 具有抗肿瘤活性。

Product Citations

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  BMC Biol. 2021 May 20;19(1):108.

  Very long intergenic non-coding (vlinc) RNAs directly regulate multiple genes in cis and trans
  BMN673 (Talazoparib) purchased from AbMole

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  Clin Cancer Res. 2020 Oct 15;26(20):5462-5476.

  A Preclinical Trial and Molecularly Annotated Patient Cohort Identify Predictive Biomarkers in Homologous Recombination-deficient Pancreatic Cancer
  BMN673 (Talazoparib) purchased from AbMole

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  Proc Natl Acad Sci U S A. 2019 Nov 5;116(45):22609-22618.

  DNA methyltransferase inhibitors induce a BRCAness phenotype that sensitizes NSCLC to PARP inhibitor and ionizing radiation.
  BMN673 (Talazoparib) purchased from AbMole

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  Nat Commun. 2019 Dec 20;10(1):5799.

  Novel approach reveals genomic landscapes of single-strand DNA breaks with nucleotide resolution in human cells.
  BMN673 (Talazoparib) purchased from AbMole

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  US Patent. 2019 Jul 30.

  THERAPY REGIMEN AND METHODS TO SENSITIZE CANCER CELLS TREATED WITH EPIGENETIC THERAPY TO PARP INHIBITORS IN MULTIPLE CANCERS
  BMN673 (Talazoparib) purchased from AbMole

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  Nat Commun. 2018 Nov 12;9(1):4760.

  Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors.
  BMN673 (Talazoparib) purchased from AbMole

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  Cancer Cell. 2016 Oct 10;30(4):637-650.

  Enhancing the Cytotoxic Effects of PARP Inhibitors with DNA Demethylating Agents – A Potential Therapy for Cancer
  BMN673 (Talazoparib) purchased from AbMole

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  Cancer Lett. 2015 Aug 1;364(1):8-16.

  Increased in vitro and in vivo sensitivity of BRCA2-associated pancreatic cancer to the poly(ADP-ribose) polymerase-1/2 inhibitor BMN 673.
  BMN673 (Talazoparib) purchased from AbMole

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  Cell Rep. 2014 Nov 6;9(3):829-41.

  Targeting the DNA repair pathway in Ewing sarcoma.
  BMN673 (Talazoparib) purchased from AbMole

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).

	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

	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.

	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)

	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."

	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.

	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.

	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.

	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 K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

Chemical Information

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.