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Product Data?SheetTalazoparibCat. No.:CAS No.:分?式:分?量:作?靶点:作?通路:储存?式:HY-161061207456-01-6C??H??F?N?O380.35PARPCell Cycle/DNA Damage; EpigeneticsPowderIn solvent-20°C4°C-80°C-20°C3 years2 years6 months1 monthInhibitors?Agonists?Screening Libraries溶解性数据体外实验DMSO : 33.33 mg/mL (87.63 mM; Need ultrasonic)H2O : < 0.1 mg/mL (insoluble)Mass1 mg5 mg10 mgSolventConcentration制备储备液1 mM5 mM10 mM2.6292 mL0.5258 mL0.2629 mL13.1458 mL2.6292 mL1.3146 mL26.2916 mL5.2583 mL2.6292 mL请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；?旦配成溶液，请分装保存，避免反复冻融造成的产品失效。储备液的保存?式和期限：-80°C, 6 months; -20°C, 1 month。-80°C 储存时，请在 6 个?内使?，-20°C 储存时，请在 1 个?内使?。体内实验请根据您的实验动物和给药?式选择适当的溶解?案。以下溶解?案都请先按照 In Vitro ?式配制澄清的储备液，再依次添加助溶剂： 为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的?作液，建议您现?现配，当天使?； 以下溶剂前显?的百分?是指该溶剂在您配制终溶液中的体积占?；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的?式助溶1. 请依序添加每种溶剂：?10% DMSO ?? 40% PEG300 ?? 5% Tween-80 ?? 45% salineSolubility: ≥ 2.5 mg/mL (6.57 mM); Clear solution此?案可获得 ≥ 2.5 mg/mL (6.57 mM，饱和度未知) 的澄清溶液。 以 1 mL ?作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；向上述体系中加? 50 μL Tween-80，混合均匀；然后继续加? 450 μL ?理盐?定容? 1 mL。Page 1 of 2 www.MedChemExpress.cn

BIOLOGICAL ACTIVITY

?物活性IC?? & Target

Talazoparib (BMN-673) 是?效的 PARP1/2 抑制剂，Ki 值分别为 1.2 nM 和 0.87 nM。PARP20.87 nM (Ki)

体外研究

PARP11.2 nM (Ki)

Talazoparib (BMN 673) demonstrates excellent potency, inhibiting PARP1 and PARP2 enzyme activity with Ki=1.2 and 0.87 nM, respectively[1]. Talazoparib (BMN 673) exhibits selective antitumor cytotoxicity and elicits DNA repair biomarkers at much lower concentrations than earlier generation PARP1/2 inhibitors (such as AZD2281, Rucaparib, and Veliparib)[2].

体内研究

Talazoparib (BMN 673; 1 mg/kg, p.o.) is orally available, displaying favorable pharmacokinetic (PK) properties and remarkable antitumor efficacy in the BRCA1 mutant MX-1 breast cancer xenograft model following oral administration as a single-agent or in combination with chemotherapy agents such as NSC 362856 and CDDP[1]. Talazoparib (BMN 673) is readily orally bioavailable, with more than 40% absolute oral bioavailability in rats when dosed in carboxylmethyl cellulose. Oral administration of Talazoparib elicits remarkable antitumor activity, xenografted tumors that carry defects in DNA repair due to BRCA mutations or PTEN deficiency are profoundly sensitive to oral Talazoparib treatment at well-tolerated doses in mice[2].

PROTOCOL

Kinase Assay [1]

The ability of a test compound to inhibit PARP1 enzyme activity is assessed using PARP1 assay kit. IC50 values are calculated using GraphPad Prism5 software. For PARP inhibitor Ki determination, enzyme assays are conducted in 96-well FlashPlate with 0.5 U of PARP1 enzyme, 0.25× activated DNA, 0.2 μCi [3H]NAD, and 5 μM cold NAD in a final volume of 50 μL in reaction buffer containing 10% glycerol (v/v), 25 mM HEPES, 12.5 mM MgCl2, 50 mM KCl, 1 mM dithiothreitol (DTT), and 0.01% NP-40 (v/v), pH 7.6. Reactions are initiated by adding NAD to the PARP reaction mixture with or without inhibitors and incubated for 1 min at room temperature. Fifty microliters of ice-cold 20% trichloroacetic acid (TCA) is then added to each well to quench the reaction. The plate is sealed and shaken for a further 120 min at room temperature, followed by centrifugation. Radioactive signal bound to the FlashPlate is determined using TopCount. PARP1 Km is determined using the Michaelis-Menten equation from various substrate concentrations (1-100 μM NAD). Compound Ki is calculated from the enzyme inhibition curve according to the following formula: Ki=IC50/[1+(substrate)/Km]. Km for PARP2 enzyme and compound Ki are determined with the same assay protocol except that 30 ng of PARP2, 0.25× activated DNA, 0.2 μCi [3H]NAD, and 20 μM cold NAD are used in the reaction for 30 min at room temperature[1].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Assay [1]

In single-agent assays, Capan-1 cells (BRCA2-deficient), MX-1 (BRCA1-deficient) cells, or other cultured cells are seeded at densities that allow linear growth for 10-12 days in 96-well plates (typically 500-3000 cells/well). Cells are treated in their recommended growth media containing varying concentrations of PARP inhibitors (Veliparib, Rucaparib, Niraparib, AZD2281, and Talazoparib) for 10-12 consecutive days (media are changed with fresh compounds every 5 days). IC50 values are calculated using GraphPad Prism5[1].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal

Administration [1]

Mice[1]

MX-1 tumor xenografts are prepared. When tumors reach an average volume of approximately 150 mm3, AZD2281 (100 mg/kg), Talazoparib (1 mg/kg), or vehicle is administered in a single po dose. Tumors are harvested at 2, 8, and 24 h after drug dosing and snap-frozen in liquid nitrogen. Tumor tissue is then homogenized in PBS on ice and extracted with lysis buffer (25 mM Tris, pH 8.0, 150 mM NaCl, 5 mM EDTA, 2 mM EGTA, 25 mM NaF, 2 mM Na3VO4, 1 mM Pefabloc, 1% Triton X-100, and protease inhibitor cocktail) containing 1% SDS. Levels of PAR in the tumor lysates

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are determined by ELISA using PARP in vivo PD assay II kit.

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

客户使?本产品发表的科研?献

????Cancer Discov. 2017 Sep;7(9):984-998.????Mol Cell. 2017 May 18;66(4):503-516.e5.????Nat Commun.?2019 Jun 11;10(1):2556.?????Clin Cancer Res. 2017 Feb 15;23(4):1001-1011.

????ACS Appl Mater Interfaces. 2019 Apr 3;11(13):12342-12356.See more customer validations on www.MedChemExpress.cnREFERENCES

[1].?Wang B, et al. Discovery and Characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent. J Med Chem. 2016 Jan 14;59(1):335-57.

[2].?Shen Y, et al. BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency.Clin Cancer Res. 2013 Sep 15;19(18):5003-15.

McePdfHeightCaution: Product has not been fully validated for medical applications. For research use only.

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