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| Targets |
PARP
(8R,9S)-Talazoparib targets poly(ADP-ribose) polymerase 1 (PARP1) and PARP2, nuclear enzymes involved in DNA repair, specifically the base excision repair pathway. PARP1/2 catalyze the synthesis of poly(ADP-ribose) (PAR) chains on target proteins, facilitating the recruitment of DNA repair machinery to sites of DNA damage. By inhibiting PARP1/2, Talazoparib traps PARP1 on DNA, preventing DNA repair and leading to the accumulation of DNA double-strand breaks. In cells with BRCA1/2 mutations, which have deficient homologous recombination repair, PARP inhibition results in synthetic lethality and cancer cell death. The (8R,9S)-enantiomer shows PARP1 inhibition with an IC₅0 of 144 nM. |
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| ln Vitro |
In a cellular PARylation experiment, (8R,9S)-Talazoparib exhibits an EC50 of 864 nM [1]. In Capan-1 cells (a BRCA2 mutation), (8R,9S)-Talazoparib had an EC50 of 1135 nM [1].
In vitro, (8R,9S)-Talazoparib inhibits PARP1 activity with an IC₅0 of 144 nM. The compound demonstrates potent PARP trapping activity, stabilizing PARP1 on DNA lesions and preventing DNA repair. In cellular assays using BRCA-deficient cancer cell lines (e.g., MDA-MB-436, SUM149PT), (8R,9S)-Talazoparib induces DNA damage, cell cycle arrest, and apoptosis at nanomolar concentrations. The compound shows cytotoxicity in cells with homologous recombination repair deficiencies while sparing normal cells. Talazoparib exhibits favorable metabolic stability and pharmacokinetic properties. |
| ln Vivo |
In vivo, Talazoparib (parent compound) has demonstrated potent antitumor activity in xenograft models of BRCA-mutated breast and ovarian cancers. The compound is orally bioavailable with favorable pharmacokinetic properties. Talazoparib is clinically approved (brand name Talzenna) for the treatment of germline BRCA-mutated, HER2-negative metastatic breast cancer. The (8R,9S)-enantiomer represents the active stereoisomer of the drug. In clinical studies, Talazoparib has shown significant efficacy in patients with BRCA-mutated breast cancer, with improvements in progression-free survival compared to chemotherapy.
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| Enzyme Assay |
In vitro enzyme assays for (8R,9S)-Talazoparib involve measuring PARP1 activity using recombinant human PARP1 enzyme. The assay is performed in 96-well plates using a PARP assay kit (e.g., colorimetric or chemiluminescent). The enzyme is incubated with varying concentrations of (8R,9S)-Talazoparib (0.001-10 microM) in assay buffer containing NAD+ and histone substrate. After incubation at room temperature for 30-60 minutes, PARylated proteins are captured on antibody-coated plates, and PAR formation is detected using a streptavidin-HRP conjugate and chromogenic substrate. IC₅0 values are determined from dose-response curves. PARP trapping activity is assessed by measuring the retention of PARP1 on DNA in cell-based assays.
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| Cell Assay |
Cellular assays for (8R,9S)-Talazoparib are performed using cancer cell lines with BRCA1/2 mutations (e.g., MDA-MB-436, SUM149PT, HCC1937) and BRCA-proficient cell lines as controls. Cells are cultured in appropriate medium and seeded in 96-well plates. Cells are treated with serial dilutions of (8R,9S)-Talazoparib (0.001-10 microM) for 72-120 hours. Cell viability is measured using CellTiter-Glo or MTT assays. IC₅0 values for cytotoxicity are calculated. DNA damage is assessed by gamma-H2AX immunofluorescence or Western blotting. Apoptosis is evaluated by caspase-3/7 activity and PARP cleavage. Cell cycle analysis is performed by flow cytometry after propidium iodide staining.
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| Animal Protocol |
In vivo animal studies for Talazoparib are conducted in xenograft mouse models of BRCA-mutated breast and ovarian cancers. Female nude mice are injected subcutaneously with cancer cells (e.g., MDA-MB-436, SUM149PT). When tumors reach approximately 100-200 mm3, mice are randomized into treatment groups (n=6-10 per group). Talazoparib is administered orally at doses of 0.1-1 mg/kg daily. Tumor volume and body weight are monitored 2-3 times per week. At study termination, tumors are excised, weighed, and processed for histological analysis (H&E, Ki67 immunohistochemistry, TUNEL). Pharmacokinetic parameters are determined from plasma samples by LC-MS/MS.
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| ADME/Pharmacokinetics |
(8R,9S)-Talazoparib (CAS#: 1207456-00-5) has molecular formula C2₆H22FN₇O2 and molecular weight 483.50. The compound is an enantiomer of Talazoparib (BMN-673), a highly potent PARP1/2 inhibitor. The (8R,9S)-enantiomer is a PARP1 inhibitor with an IC₅0 of 144 nM. Talazoparib is clinically approved (Talzenna) for the treatment of BRCA-mutated breast cancer. The compound is soluble in DMSO at ≥30 mg/mL. Storage should be at -20degC. For research use only, not for human therapeutic applications without appropriate authorization.
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| References | |
| Additional Infomation |
We have discovered and developed a series of novel tetrahydropyridophthalazinone compounds as inhibitors of poly(ADP-ribose) polymerases (PARP) 1 and 2. Lead compound optimization screening identified (8S,9R)-47 (taporazopanib; BMN 673; (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). This compound's unique stereospecific biphasic central intercalation structure enables it to bind extensively and uniquely to PARP1/2 proteins. (8S,9R)-47 exhibits excellent inhibitory activity, with inhibition constants Ki of 1.2 nM for PARP1 and 0.87 nM for PARP2 enzyme activity. (8S,9R)-47 inhibited PARP-mediated parylation in whole-cell experiments with an EC50 of 2.51 nM and inhibited the proliferation of cancer cells carrying mutant BRCA1/2 with EC50s of 0.3 nM (MX-1) and 5 nM (Capan-1), respectively. (8S,9R)-47 is orally available and has good pharmacokinetic (PK) characteristics. In a BRCA1 mutant MX-1 breast cancer xenograft model, it showed significant antitumor efficacy when taken orally as a monotherapy or in combination with chemotherapy drugs such as temozolomide and cisplatin. (8S,9R)-47 has completed a phase I clinical trial and is currently undergoing phase II and III clinical trials for the treatment of locally advanced and/or metastatic breast cancer carrying germline BRCA1/2 pathogenic mutations. [1]
(8R,9S)-Talazoparib (CAS#: 1207456-00-5), also known as (8R,9S)-BMN-673, is an enantiomer of Talazoparib, a highly potent poly(ADP-ribose) polymerase (PARP) inhibitor. PARP1/2 are nuclear enzymes involved in DNA repair, and PARP inhibitors are used to treat cancers with BRCA mutations or other homologous recombination repair deficiencies. Talazoparib (trade name: Talzenna) is clinically approved for the treatment of germline BRCA-mutated, HER2-negative metastatic breast cancer. The (8R,9S)-enantiomer is a PARP1 inhibitor with an IC₅0 of 144 nM. The compound is used in research to study PARP inhibition, DNA repair, and cancer biology. |
| Molecular Formula |
C19H14F2N6O
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|---|---|
| Molecular Weight |
380.4
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| Exact Mass |
380.12
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| Elemental Analysis |
C, 60.00; H, 3.71; F, 9.99; N, 22.10; O, 4.21
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| CAS # |
1207456-00-5
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| Related CAS # |
Talazoparib tosylate;1373431-65-2;Talazoparib;1207456-01-6
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| PubChem CID |
135742498
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| Appearance |
White to off-white solid powder
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| LogP |
1.898
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
28
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| Complexity |
654
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| Defined Atom Stereocenter Count |
2
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| InChi Key |
HWGQMRYQVZSGDQ-HOTGVXAUSA-N
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| InChi Code |
InChI=1S/C19H14F2N6O/c1-27-18(22-8-23-27)15-16(9-2-4-10(20)5-3-9)24-13-7-11(21)6-12-14(13)17(15)25-26-19(12)28/h2-8,15-16,24H,1H3,(H,26,28)/t15-,16-/m0/s1
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| Chemical Name |
(11R,12S)-7-fluoro-11-(4-fluorophenyl)-12-(2-methyl-1,2,4-triazol-3-yl)-2,3,10-triazatricyclo[7.3.1.05,13]trideca-1,5(13),6,8-tetraen-4-one
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| Synonyms |
1207456-00-5; (8R,9S)-Talazoparib; BMN-673 8R,9S; (8r,9s)-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; BMN-673 (8R,9S); CHEMBL3764816; (8R,9S)-BMN-673; LT-674;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ≥ 50 mg/mL (~131.46 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.57 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.57 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6288 mL | 13.1441 mL | 26.2881 mL | |
| 5 mM | 0.5258 mL | 2.6288 mL | 5.2576 mL | |
| 10 mM | 0.2629 mL | 1.3144 mL | 2.6288 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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