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Purity: ≥98%
TAK-960 DiHCl, the dihydrochloride salt of TAK960, is an orally bioavailable, potent, and selective PLK1 polo-like kinase 1 (PLK1) inhibitor with an IC50 of 0.8 nM at 10 μM ATP.
| Targets |
PLK1 (IC50 = 0.8 nM); PLK2 (IC50 = 16.9 nM); PLK3 (IC50 = 50.2 nM); FAK/PTK2 (IC50 = 19.6 nM); MLCK/MYLK (IC50 = 25.6 nM); FES/FPS (IC50 = 58.2 nM);
TAK-960 dihydrochloride treatment results in increased phosphorylation of histone H3 (pHH3), aberrant polo mitosis morphology, and accumulation of G2-M cells. With mean EC50 values ranging from 8.4 to 46.9 nM, TAK-960 dihydrochloride (2-1000 nM; 72 hours) inhibits the proliferation of multiple cancer cell lines, but not nondividing normal cells[1]. TAK-960 dihydrochloride (8 nM) causes G2/M cell cycle arrest without causing appreciable cytotoxicity in HeLa cells[2]. |
|---|---|
| ln Vitro |
TAK-960 dihydrochloride treatment results in increased phosphorylation of histone H3 (pHH3), aberrant polo mitosis morphology, and accumulation of G2-M cells. With mean EC50 values ranging from 8.4 to 46.9 nM, TAK-960 dihydrochloride (2-1000 nM; 72 hours) inhibits the proliferation of multiple cancer cell lines, but not nondividing normal cells[1].
TAK-960 dihydrochloride (8 nM) causes G2/M cell cycle arrest without causing appreciable cytotoxicity in HeLa cells[2]. TAK-960 inhibits proliferation of multiple human cancer cell lines with mean EC₅₀ values ranging from 8.4 to 46.9 nmol/L, while showing minimal effect on nondividing normal human lung fibroblasts MRC5 (EC₅₀ >1,000 nmol/L).[1] Treatment induces G₂-M phase accumulation and increases phosphorylation of histone H3 (pHH3) in HT-29 colorectal cancer cells.[1] Immunofluorescence reveals aberrant mitotic spindle formation (monopolar spindles) in HT-29 cells after 24-hour treatment with TAK-960.[1] Potency is not affected by TP53 or KRAS mutation status or by overexpression of multidrug resistance protein 1 (MDR1) in cancer cell lines such as HCT-15, COLO320DM, and K562ADR.[1] |
| ln Vivo |
TAK-960 dihydrochloride shows notable efficacy against multiple tumor xenografts (10 mg/kg; p.o.; once daily for 2 weeks)[1].
TAK-960 dihydrochloride (p.o.) in animal models significantly inhibits the growth of HT-29 colorectal cancer xenografts and raises pHH3 in a dose-dependent manner[1]. Oral administration of TAK-960 significantly inhibits tumor growth in multiple xenograft models, including HT-29 colorectal cancer, HCT116, PC-3, BT474, A549, NCI-H1299, NCI-H1975, A2780, and MV4-11 tumors.[1] TAK-960 induces pHH3 in tumors in a dose-dependent manner, indicating PLK1 inhibition and mitotic arrest in vivo.[1] In a disseminated leukemia model (MV4-11luc), TAK-960 treatment (7.5 mg/kg QD×9) significantly prolongs median survival compared to vehicle (39.5 vs. 25 days).[1] TAK-960 retains antitumor activity in MDR1-overexpressing K562ADR xenografts, whereas paclitaxel does not.[1] |
| Enzyme Assay |
The inhibitory activity of TAK-960 against PLK1 was assessed using a TR-FRET assay measuring ATP-dependent phosphorylation of a biotinylated mTOR-derived peptide.[1]
Selectivity profiling across 288 kinases was performed using a HotSpot kinase assay, with IC₅₀ values determined for kinases inhibited >80% at 1,000 nmol/L TAK-960.[1] |
| Cell Assay |
After adding 10% fetal calf serum to the suitable medium, 3,000–30,000 cells are seeded into each well of 96-well plates. The CellTiter-Glo Assay is used to determine the number of viable cells after treating the cells with TAK-960 serial dilutions for 24 hours. A 72-hour analysis is conducted. With GraphPad Prism, EC50 values are calculated and statistical analysis is performed.
Cell cycle analysis was performed by treating HT-29 cells with TAK-960 for 48 hours, fixing with ethanol, staining with propidium iodide, and analyzing DNA content via flow cytometry.[1] Immunocytochemistry was conducted on HT-29 cells treated with TAK-960 for 24 hours, fixed, permeabilized, and stained with antibodies against α-tubulin and γ-tubulin, with DAPI for nuclei.[1] Cell proliferation was assessed using a luminescent cell viability assay after 72-hour treatment with TAK-960 in 96-well plates.[1] pHH3 levels were measured by ELISA in cell lysates after 24-hour treatment.[1] |
| Animal Protocol |
nude mice or SCID mice (bearing HCT116, PC-3, BT474, A549, NCI-H1299, NCI-H1975, A2780, and MV4-11 cells)[1]
10 mg/kg P.o.; once daily for 2 weeks For subcutaneous xenograft models, mice were implanted with cancer cells and randomized when tumor volumes reached ~200 mm³. TAK-960 was suspended in 0.5% methyl cellulose and administered orally at doses ranging from 6.25 to 30 mg/kg on various schedules (e.g., QD×21, QD×3/w×3w, Q2D×2/w×3w).[1] In the disseminated leukemia model, NOD/SCID mice were irradiated, injected with MV4-11luc cells via tail vein, and treated with TAK-960 orally at 7.5 mg/kg QD×9.[1] Paclitaxel and AraC were administered intraperitoneally in saline.[1] |
| ADME/Pharmacokinetics |
Following oral administration to tumor-bearing mice, TAK-960 showed dose-proportional plasma exposure and preferential distribution in tumor tissue. [1] Peak drug concentrations in tumor tissue occurred 4–8 hours after administration, while pHH3-induced peaks occurred at 24 hours, indicating a delayed pharmacodynamic response. [1]
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| Toxicity/Toxicokinetics |
In in vivo studies of delayed tumor growth, oral administration of 10 mg/kg TAK-960 to mice in combination with radiotherapy did not cause significant weight loss or significant side effects. [2] The dose of 10 mg/kg was determined to be the maximum dose that would not affect tumor growth rate when administered alone. [2]
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| References |
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| Additional Infomation |
TAK-960, an oral Polo-like kinase 1 (PLK1) inhibitor, has potential antitumor activity. TAK-960 selectively inhibits PLK1, inducing selective G2/M phase cell cycle arrest in various tumor cells, followed by apoptosis; while in normal cells, TAK-960 causes reversible G1 and G2 phase cell cycle arrest but does not induce apoptosis. PLK1 inhibition may lead to suppression of the proliferation of PLK1-overexpressing tumor cells. PLK1, named after the polo gene in Drosophila, is a serine/threonine kinase that plays a crucial role in the regulation of mitosis. TAK-960 is an orally bioavailable PLK1 inhibitor that has shown broad-spectrum antitumor activity in preclinical models, including tumors resistant to paclitaxel and doxorubicin due to MDR1 overexpression. [1] It has entered a phase I clinical trial in patients with advanced cancer. [1]
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| Molecular Formula |
C27H36CL2F3N7O3
|
|---|---|
| Molecular Weight |
561.59916
|
| Exact Mass |
561.267
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| Elemental Analysis |
C, 57.74; H, 6.10; F, 10.15; N, 17.46; O, 8.55
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| CAS # |
1137868-52-0
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| Related CAS # |
TAK-960 dihydrochloride;TAK-960 hydrochloride;1137868-96-2;TAK-960 monohydrochloride;2108449-45-0
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| PubChem CID |
53357478
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| Appearance |
White to beige solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.615
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| LogP |
1.33
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
40
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| Complexity |
903
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| Defined Atom Stereocenter Count |
0
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| SMILES |
0
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| InChi Key |
GWRSATNRNFYMDI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H34F3N7O3/c1-35-10-8-16(9-11-35)32-24(38)18-12-22(40-3)20(13-19(18)28)33-26-31-14-21-23(34-26)37(17-6-4-5-7-17)15-27(29,30)25(39)36(21)2/h12-14,16-17H,4-11,15H2,1-3H3,(H,32,38)(H,31,33,34)
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| Chemical Name |
4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide
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| Synonyms |
TAK-960; TAK960 dihydrochloride; TAK 960 dihydrochloride
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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) |
H2O: ~10 mg/mL (~15.8 mM)
DMSO: ~3.2 mg/mL (~5.1 mM） |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7806 mL | 8.9031 mL | 17.8063 mL | |
| 5 mM | 0.3561 mL | 1.7806 mL | 3.5613 mL | |
| 10 mM | 0.1781 mL | 0.8903 mL | 1.7806 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.
 TAK-960 is a potent and selective inhibitor of PLK1.Mol Cancer Ther. 2012 Mar;11(3):700-9. |
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 TAK-960 induces accumulation of aberrant mitotic cells in HT-29 cells.Mol Cancer Ther. 2012 Mar;11(3):700-9. |
 PK/PD and antitumor activity analysis for TAK-960 in mice bearing HT-29 colorectal cancer cells.Mol Cancer Ther. 2012 Mar;11(3):700-9. |
 Single-agent efficacy of TAK-960 in various tumor xenograft models using human cancer cell lines.Mol Cancer Ther. 2012 Mar;11(3):700-9. |
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 TAK-960 inhibits proliferation of human cancer cell lines regardless ofTP53andKRASmutation and MDR1 expression status. |
 TAK-960 shows PD activity in paclitaxel-resistant model.Mol Cancer Ther. 2012 Mar;11(3):700-9. |
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