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    Talazoparib (BMN 673; MDV3800)
    Talazoparib (BMN 673; MDV3800)

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0304
    CAS #: 1207456-01-6 Purity ≥98%

    Description: Talazoparib (formerly BMN-673 and MDV-3800; trade name: Talzenna), is a novel, highly potent and orally bioavailable PARP1/2 [poly(ADP-ribose) polymerase] inhibitor approved for cancer treatment. It has favorable metabolic stability, oral bioavailability, and pharmacokinetic properties. As a novel PARP inhibitor, Talazoparib has an 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. On Oct 16 2018, Talazoparib was approved by the US FDA for the treatment of locally advanced or metastatic breast cancer patients with a germline BRCA mutation. 

    References: Clin Cancer Res. 2013 Sep 15;19(18):5003-15; Clin Cancer Res. 2014 Apr 15;20(8):2237.

    Related CAS: 1373431-65-2 (tosylate); 1207454-56-5; 1207456-00-5 (racemic mixture); 1207456-01-6 (free base)

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    Molecular Weight (MW)380.35
    FormulaC19H14F2N6O
    CAS No.1207456-01-6 (free base); 
    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
    Other info

    Chemical Name: (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

    SMILES Code: O=C1NN=C2C3=C1C=C(F)C=C3N[[email protected]](C4=CC=C(F)C=C4)[[email protected]]2C5=NC=NN5C

    SynonymsBMN 673; BMN673; MDV-3800; MDV 3800; MDV3800; BMN-673; LT673; LT 673; LT-673; Talazoparib; trade name: Talzenna


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    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 VivoIn 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 modelNude mice bearing established subcutaneous MX-1 tumor xenografts.
    Formulation & Dosage0.33 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.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    Talazoparib (BMN 673)

    BMN 673 is a potent PARP inhibitor.  2013 Sep 15;19(18):5003-15.

     

    Talazoparib (BMN 673)

    A, siRNAs targeting homologous recombination genes sensitize to PARP1/2 inhibitors.  2013 Sep 15;19(18):5003-15.

     

    Talazoparib (BMN 673)

    BMN 673 exhibits antitumor activity against a BRCA-mutant tumor model in mice.  2013 Sep 15;19(18):5003-15.

     

    Talazoparib (BMN 673)

    BMN 673 potentiates the effects of DNA-damaging cytotoxic agents.  2013 Sep 15;19(18):5003-15.

     

    Talazoparib (BMN 673)

    Talazoparib (BMN 673)



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