product name Talazoparib (BMN 673)
Description: Talazoparib, also known as BMN-673 and MDV-3800, is a novel PARP inhibitor with IC50 of 0.58 nM in a cell-free assay. It selectively binds to PARP and prevents PARP-mediated DNA repair of single strand DNA breaks via the base-excision repair pathway. This enhances the accumulation of DNA strand breaks, promotes genomic instability and eventually leads to apoptosis.
References: Clin Cancer Res. 2013 Sep 15;19(18):5003-15; Clin Cancer Res. 2014 Apr 15;20(8):2237.
380.35
Formula
C19H14F2N6O
CAS No.
1207456-01-6
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 38 mg/mL (99.9 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
Synonyms
BMN 673, BMN 673
other peoduct :
| In Vitro |
In vitro activity: BMN-673 selectively binds to PARP and prevents PARP-mediated DNA repair of single strand DNA breaks via the base-excision repair pathway. This enhances the accumulation of DNA strand breaks, promotes genomic instability and eventually leads to apoptosis. BMN 673 selectively kills cancer cells with BRCA-1 or BRCA-2 mutations. BMN 673 demonstrates single-agent cytotoxicityin BRCA-1 mutant (MX-1, IC50 = 0.3 nM) and BRCA-2 mutant cells (Capan-1, IC50 = 5 nM). In contrast, in MRC-5 normal human fibroblastand other tumor cell lines with wild-type BRCA-1 and BRCA-2 genes, IC50 of BMN 673 ranges between 90 nM and 1.9 μM. In cultured human cancer cells, BMN 673 also significantly enhances the cytotoxic efficacy of both Temozolomide and SN-38. Off-target molecular screening did not identify significant non-specific activity for this class of PARP inhibitors. Kinase Assay: For PARP inhibitor Ki determination, enzyme assays were conducted in 96-well FlashPlate with 0.5 U PARP1 enzyme , 0.25x activated DNA, 0.2 mCi [3H] NAD, and 5 mmol/L cold NAD(Sigma) in a final volume of 50 mL reaction buffer containing 10% glycerol (v/v), 25 mmol/L HEPES, 12.5 mmol/L MgCl2, 50 mmol/L KCl, 1 mmol/L dithiothreitol (DTT), and 0.01% NP-40 (v/v), pH 7.6. Reactions were initiated by adding NAD to the PARP reaction mixture with or without inhibitors and incubated for 1 minute at room temperature. Fifty microliter of ice-cold 20% trichloroacetic acid (TCA) was then added to each well to stop the reaction. The plate was sealed and shaken for a further 120 minutes at room temperature, followed by centrifugation. Radioactive signal bound to the FlashPlate was determined using Top-Count. PARP1 Km was determined using Michaelis–Menten equation from various substrate concentrations (1–100 mmol/L NAD). Compound Ki was calculated from enzyme inhibition curve according to the formula: Ki ¼ IC50/[1þ (substrate)/Km]. Km for PARP2 enzyme and compound Ki were determined with the same assay protocol except 30 ng PARP2, 0.25x activated DNA, 0.2 mCi [3H] NAD, and 20 mmol/L cold NAD were used in the reaction for 30 minutes at room temperature. Cell Assay: BMN 673 exhibits a potent inhibitory effect on a panel of 11 SCLC cell lines (IC50=1.7 to 15 nmol/L), which are all within clinically achievable ranges. In addition, sensitivity to BMN673 correlates to DNA repair protein expression and PI3K pathway activity. |
|---|---|
| In Vivo | In rat pharmacokinetic studies, BMN 673 displays >50% oralbioavailability and pharmacokinetic properties that enable singledaily dosing. In MX-1 xenograft tumor model studies, daily oral dosingof BMN 673 significantly enhances the antitumor effects ofcytotoxic therapies in a dose-dependent manner. |
| Animal model | Nude mice bearing established subcutaneous MX-1 tumor xenografts. |
| Formulation & Dosage | 0.33 and 0.1 mg/kg; Oral gavage and twice daily for 28 consecutive days. |
| References | Clin Cancer Res. 2013 Sep 15;19(18):5003-15; Clin Cancer Res. 2014 Apr 15;20(8):2237; Mol Cancer Ther. 2014 Feb;13(2):433-43; Clin Cancer Res. 2013 Nov 15;19(22):6322-8. |
