Talazoparib (BMN-673) 他拉唑帕尼

生物活性

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 (BMN-673) 不抑制PARG，对PTEN突变型高度敏感。BMN-673 选择性与PARP 结合，且抑制PARP-介导的通过碱基切除修复途径的单链DNA断裂的修复。增强了DNA链断裂的积累，促进基因组不稳定性，并最终导致细胞凋亡。BMN 673选择性杀死BRCA-1或BRCA-2突变的癌细胞。

在体内，Talazoparib（0.33 mg/kg；i.g.；每日一次；持续28天）对小鼠的BRCA1突变乳腺癌模型表现出抗肿瘤活性。

使用AbMole产品发表的文献

• cancers. 2023 Aug 16.

  Development of a Patient-Derived 3D Immuno-Oncology Platform to Potentiate Immunotherapy Responses in Ascites-Derived Circulating Tumor Cells

• Front Oncol. 2023 May 9;13:1175617.

  Sustained delivery of PARP inhibitor Talazoparib for the treatment of BRCA-deficient ovarian cancer

• Front Oncol. 2022 Aug 16;12:940377.

  Effectiveness of PARP inhibition in enhancing the radiosensitivity of 3D spheroids of head and neck squamous cell carcinoma

• BMC Biol. 2021 May 20;19(1):108.

  Very long intergenic non-coding (vlinc) RNAs directly regulate multiple genes in cis and trans

• 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

• Nat Commun. 2019 Dec 20;10(1):5799.

  Novel approach reveals genomic landscapes of single-strand DNA breaks with nucleotide resolution in human cells.

• 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.

• US Patent. 2019 Jul 30.

  THERAPY REGIMEN AND METHODS TO SENSITIZE CANCER CELLS TREATED WITH EPIGENETIC THERAPY TO PARP INHIBITORS IN MULTIPLE CANCERS

• Nat Commun. 2018 Nov 12;9(1):4760.

  Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors.

• University of Maryland. 2017.

  Developing a Novel Combination Therapy and Elucidating Mechanisms of Increased ALT-NHEJ in Acute Myeloid Leukemia

• 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

• 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.

• Cell Rep. 2014 Nov 6;9(3):829-41.

  Targeting the DNA repair pathway in Ewing sarcoma.

产品使用成果展示

	数据来源	Cancer Cell (2016). Figure 4. BMN 673 (Abmole Bioscience)
	方法
	细胞系/动物模型	TNBC cells
	浓度	1–5 nM
	处理时间	72 h
	实验结果	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).

	数据来源	Cancer Cell (2016). Figure 3. BMN 673 (Abmole Bioscience)
	方法	MTS assay
	细胞系/动物模型	MDA-MB-231 cells, MOLM14 cells
	浓度	2.5–20 nM
	处理时间	72 h
	实验结果	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).

	数据来源	Cancer Cell (2016). Figure 2. BMN 673 (Abmole Bioscience)
	方法
	细胞系/动物模型	MDA-MB-231 cells, MOLM14 cells
	浓度	10 nM
	处理时间	72 h
	实验结果	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.

	数据来源	Cancer Cell (2016). Figure 1. BMN 673 (Abmole Bioscience)
	方法
	细胞系/动物模型	MOLM14 cells
	浓度	1, 2.5, and 5 nM
	处理时间	72 h
	实验结果	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).

	数据来源	McGill University (2015). Figure S2.BMN 673 (Abmole Biosciences, Hong Kong, China).
	方法	Cells were plated in 6-well plates at 2x104 cells/well and treated 24 h later with veliparib, cisplatin or BMN 673.
	细胞系/动物模型	Capan-1 (HTB-79), MIA PaCa-2 (CRL-1420) and PANC-1 (CRL-1469)
	浓度
	处理时间	24 h
	实验结果	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

	数据来源	McGill University (2015). Figure 5.BMN 673 (Abmole Biosciences, Hong Kong, China).
	方法	Cells were plated in 6-well plates at 2x104 cells/well and treated 24 h later with veliparib, cisplatin or BMN 673.
	细胞系/动物模型	Capan-1 (HTB-79), MIA PaCa-2 (CRL-1420) and PANC-1 (CRL-1469)
	浓度
	处理时间	24 h
	实验结果	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.

	数据来源	McGill University (2015). Figure 4.BMN 673 (Abmole Biosciences, Hong Kong, China).
	方法	Cisplatin and BMN 673 were solubilized in DMSO and diluted with PBS containing 10% dimethylacetamide and 6% Solutol.
	细胞系/动物模型	Capan-1 (HTB-79), MIA PaCa-2 (CRL-1420) and PANC-1 (CRL-1469)
	浓度	0.33 mg/kg,
	处理时间
	实验结果	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)

	数据来源	McGill University (2015). Figure 3.BMN 673 (Abmole Biosciences, Hong Kong, China).
	方法	Cisplatin and BMN 673 were solubilized in DMSO and diluted with PBS containing 10% dimethylacetamide and 6% Solutol.
	细胞系/动物模型	Capan-1 (HTB-79), MIA PaCa-2 (CRL-1420) and PANC-1 (CRL-1469)
	浓度	0.33 mg/kg,
	处理时间
	实验结果	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.

	数据来源	Cell Reports (2015). Figure 4. BMN-673 was purchased from Abmole (BMN673, 1207456-01-6)
	方法	Orthotopic EWS Xenograft Model
	细胞系/动物模型	EWS cell lines
	浓度	0.1 mg/kg
	处理时间	12–18 weeks
	实验结果	"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."

	数据来源	Cell Reports (2015). Figure 4. BMN-673 was purchased from Abmole (BMN673, 1207456-01-6)
	方法	Orthotopic EWS Xenograft Model
	细胞系/动物模型	EWS cell lines
	浓度	0.1 mg/kg
	处理时间	12–18 weeks
	实验结果	"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."

	数据来源	Cell Reports (2015). Figure 2. BMN-673 was purchased from Abmole (BMN673, 1207456-01-6)
	方法	Cell Titer Glo (Promega, G7570)
	细胞系/动物模型	EW8, ES6, SAOS2 cell lines
	浓度	0, 1, 2.5, 5, 10, 20, 50, or 100 µM
	处理时间	72hr or 144hr
	实验结果	"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."

	数据来源	Cancer Letters(2015). Figure 5. BMN 673 (Abmole Biosciences, Hong Kong, China)
	方法	Immunohistochemistry H&E staining
	细胞系/动物模型
	浓度
	处理时间
	实验结果	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.

	数据来源	Cancer Letters(2015). Figure 4. BMN 673 (Abmole Biosciences, Hong Kong, China)
	方法	Preclinical PDX trial
	细胞系/动物模型
	浓度	0.33 mg/kg, 0.05 cc, once daily
	处理时间	70 days
	实验结果	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.

	数据来源	Cancer Letters(2015). Figure 4. BMN 673 (Abmole Biosciences, Hong Kong, China)
	方法	long-term colony formation assays
	细胞系/动物模型	PANC-1 BRCA2-knockdown cell lines
	浓度	0.3125; 0.625; 1.25; 2.5; 5μM
	处理时间	10 days
	实验结果	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.

	数据来源	Cancer Letters(2015). Figure 2. BMN 673 (Abmole Biosciences, Hong Kong, China)
	方法	Real-time cell analysis (xCELLigence)
	细胞系/动物模型	Capan-1 and MIA PaCa-2
	浓度	unnoted
	处理时间	48 hours
	实验结果	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.

实验参考

体外实验*
细胞系	Capan-1 and MIA PaCa-2
方法	Real-time cell analysis (xCELLigence)
浓度
处理时间	48 h

*上述方法来自公开文献，仅供相同目的实验参考。如实验目的、材料、方法不同，请参考其他文献。

体内实验*
动物模型	Patient-derived xenograft (PDX) model
配制	Solubilized in DMSO and diluted with PBS containing 10% dimethylacetamide (Sigma-Aldrich) and 6% Solutol (Sigma-Aldrich).
剂量	0.33 mg/kg, 0.05 cc, once daily
给药处理	oral gavage

*上述方法来自公开文献，仅供相同目的实验参考。如实验目的、材料、方法不同，请参考其他文献。

化学性质

分子量	380.35
分子式	C19H14F2N6O
CAS号	1207456-01-6
溶解性（25°C）	DMSO 25 mg/mL
储存条件	粉末型式       -20°C   3年；4°C   2年 溶于溶剂       -80°C   6个月；-20°C   1个月
运输方式	冰袋运输，根据产品的不同，可能会有相应调整。

储备液配制

*下述溶液配置方法仅为基于分子量计算出的理论值。不同产品在配置溶液前，需考虑其在不同溶剂中的溶解度限制。

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	2.6292 mL	13.1458 mL	26.2916 mL
5 mM	0.5258 mL	2.6292 mL	5.2583 mL
10 mM	0.2629 mL	1.3146 mL	2.6292 mL

不同实验动物依据体表面积的等效剂量转换表（参考来源于公开文献）

	小鼠	大鼠	兔	豚鼠	仓鼠	狗
重量 (kg)	0.02	0.15	1.8	0.4	0.08	10
体表面积 (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km 系数	3	6	12	8	5	20

动物 A (mg/kg) = 动物 B (mg/kg) ×	动物 B的Km系数
	动物 A的Km系数

例如，依据体表面积折算法，将化合物用于小鼠的剂量20 mg/kg 换算成大鼠的剂量，需要将20 mg/kg 乘以小鼠的K_m系数（3），再除以大鼠的K_m系数（6），得到化合物用于大鼠的等效剂量为10 mg/kg。

参考文献

[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.