TAK-901Novel Aurora A/B inhibitor CAS# 934541-31-8 |
- TUG-770
Catalog No.:BCC2018
CAS No.:1402601-82-4
Quality Control & MSDS
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| Cas No. | 934541-31-8 | SDF | Download SDF |
| PubChem ID | 16124208 | Appearance | Powder |
| Formula | C28H32N4O3S | M.Wt | 504.64 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : 2 mg/mL (3.96 mM; Need ultrasonic and warming) | ||
| Chemical Name | 5-(3-ethylsulfonylphenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide | ||
| SMILES | CCS(=O)(=O)C1=CC=CC(=C1)C2=CC(=C(C3=C2C4=CC(=CN=C4N3)C)C)C(=O)NC5CCN(CC5)C | ||
| Standard InChIKey | WKDACQVEJIVHMZ-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C28H32N4O3S/c1-5-36(34,35)21-8-6-7-19(14-21)23-15-22(28(33)30-20-9-11-32(4)12-10-20)18(3)26-25(23)24-13-17(2)16-29-27(24)31-26/h6-8,13-16,20H,5,9-12H2,1-4H3,(H,29,31)(H,30,33) | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | TAK-901 is a novel inhibitor of Aurora A and B with IC50 value of 21 nM and 15 nM, respectively. | |||||
| Targets | Aurora A | Aurora B | ||||
| IC50 | 21 nM | 15 nM | ||||
TAK-901 Dilution Calculator
TAK-901 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 1.9816 mL | 9.9081 mL | 19.8161 mL | 39.6322 mL | 49.5403 mL |
| 5 mM | 0.3963 mL | 1.9816 mL | 3.9632 mL | 7.9264 mL | 9.9081 mL |
| 10 mM | 0.1982 mL | 0.9908 mL | 1.9816 mL | 3.9632 mL | 4.954 mL |
| 50 mM | 0.0396 mL | 0.1982 mL | 0.3963 mL | 0.7926 mL | 0.9908 mL |
| 100 mM | 0.0198 mL | 0.0991 mL | 0.1982 mL | 0.3963 mL | 0.4954 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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IC50: 0.0017, 0.021 for Aurora-B/INCENP and Aurora-A/TPX2, respectively
Protein kinases Aurora A, B, and C play crucial roles during mitosis and cell division, are frequently elevated in cancer, and represent attractive targets for therapeutic intervention. TAK-901 is a novel, multitargeted Aurora B kinase inhibitor derived from a novel azacarboline kinase hinge-binder chemotype.
In vitro: TAK-901 exhibited time-dependent, tight-binding inhibition of Aurora B, but not Aurora A. Consistently, TAK-901 suppressed cellular histone H3 phosphorylation and induced polyploidy. In various human cancer cell lines, TAK-901 inhibited cell proliferation with effective concentration values from 40 to 500 nmol/L. TAK-901 potently inhibited only a few kinases other than Aurora B in intact cells, including FLT3 and FGFR2 [1].
In vivo: In rodent xenografts, TAK-901 exhibited potent activity against multiple human solid tumor types, and complete regression was found in the ovarian cancer A2780 model. In vivo biomarker studies showed that TAK-901 induced PD responses consistent with Aurora B inhibition and correlating with retention of TAK-901 in tumor tissue. [2].
Clinical trials: An open-label, dose escalation, phase I study has been conducted to identify the MTD and PK profile of TAK-901 in adult patients with advanced solid tumors or lymphoma.
Reference:
[1] Farrell P, Shi L, Matuszkiewicz J, Balakrishna D, Hoshino T, Zhang L, Elliott S, Fabrey R, Lee B, Halkowycz P, Sang B, Ishino S, Nomura T, Teratani M, Ohta Y, Grimshaw C, Paraselli B, Satou T, de Jong R. Biological characterization of TAK-901, an investigational, novel, multitargeted Aurora B kinase inhibitor. Mol Cancer Ther. 2013;12(4):460-70.
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Biological characterization of TAK-901, an investigational, novel, multitargeted Aurora B kinase inhibitor.[Pubmed:23358665]
Mol Cancer Ther. 2013 Apr;12(4):460-70.
Protein kinases Aurora A, B, and C play essential roles during mitosis and cell division, are frequently elevated in cancer, and represent attractive targets for therapeutic intervention. TAK-901 is an investigational, multitargeted Aurora B kinase inhibitor derived from a novel azacarboline kinase hinge-binder chemotype. TAK-901 exhibited time-dependent, tight-binding inhibition of Aurora B, but not Aurora A. Consistent with Aurora B inhibition, TAK-901 suppressed cellular histone H3 phosphorylation and induced polyploidy. In various human cancer cell lines, TAK-901 inhibited cell proliferation with effective concentration values from 40 to 500 nmol/L. Examination of a broad panel of kinases in biochemical assays revealed inhibition of multiple kinases. However, TAK-901 potently inhibited only a few kinases other than Aurora B in intact cells, including FLT3 and FGFR2. In rodent xenografts, TAK-901 exhibited potent activity against multiple human solid tumor types, and complete regression was observed in the ovarian cancer A2780 model. TAK-901 also displayed potent activity against several leukemia models. In vivo biomarker studies showed that TAK-901 induced pharmacodynamic responses consistent with Aurora B inhibition and correlating with retention of TAK-901 in tumor tissue. These preclinical data highlight the therapeutic potential of TAK-901, which has entered phase I clinical trials in patients within a diverse range of cancers.
Preclinical FLT-PET and FDG-PET imaging of tumor response to the multi-targeted Aurora B kinase inhibitor, TAK-901.[Pubmed:24332383]
Nucl Med Biol. 2014 Feb;41(2):148-54.
INTRODUCTION: The Aurora kinases play a key role in mitosis and have recently been identified as attractive targets for therapeutic intervention in cancer. The aim of this study was therefore to investigate the utility of 3'-[(18)F]fluoro-3'-deoxythymidine (FLT) and 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) for assessment of tumor response to the multi-targeted Aurora B kinase inhibitor, TAK-901. METHODS: Balb/c nude mice bearing HCT116 colorectal xenografts were treated with up to 30mg/kg TAK 901 or vehicle intravenously twice daily for two days on a weekly cycle. Tumor growth was monitored by calliper measurements and PET imaging was performed at baseline, day 4, 8, 11 and 15. Tumors were harvested at time points corresponding to days of PET imaging for analysis of ex vivo markers of cell proliferation and metabolism together with markers of Aurora B kinase inhibition including phospho-histone H3 (pHH3) and senescence associated beta-galactosidase. RESULTS: Tumor growth was inhibited by 60% on day 12 of 30mg/kg TAK-901 therapy. FLT uptake was significantly reduced by day 4 of treatment and this corresponded with reduction in bromodeoxyuridine and pHH3 staining by immunohistochemistry. All biomarkers rebounded towards baseline levels by the commencement of the next treatment cycle, consistent with release of Aurora B kinase suppression. TAK-901 therapy had no impact on glucose metabolism as assessed by FDG uptake and GLUT1 staining by immunohistochemistry. CONCLUSIONS: FLT-PET, but not FDG-PET, is a robust non-invasive imaging biomarker of early HCT116 tumor response to the on-target effects of the multi-targeted Aurora B kinase inhibitor, TAK-901. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: This is the first report to demonstrate the impact of the multi-targeted Aurora B kinase inhibitor, TAK-901 on tumor FLT uptake. The findings provide a strong rationale for the evaluation of FLT-PET as an early biomarker of tumor response in the early phase clinical development of this compound.
Aurora B Inhibitor TAK-901 Synergizes with BCL-xL Inhibition by Inducing Active BAX in Cancer Cells.[Pubmed:28179288]
Anticancer Res. 2017 Feb;37(2):437-444.
BACKGROUND: Aurora B kinase plays an essential role in chromosome segregation and cytokinesis, and is dysregulated in many cancer types, making it an attractive therapeutic target. TAK-901 is a potent aurora B inhibitor that showed efficacy in both in vitro and in vivo oncology models. MATERIALS AND METHODS: We conducted a synthetic lethal siRNA screening to identify the genes that, when silenced, can potentiate the cell growth-inhibitory effect of TAK-901. RESULTS: B-cell lymphoma-extra large (BCL-xL) depletion by siRNA or chemical inhibition synergized with TAK-901 in cancer cell lines. As a mechanism of synthetic lethality, active BCL2 associated X, apoptosis regulator (BAX) was induced by TAK-901. BCL-xL protected cells from BAX-dependent apoptosis induction. Therefore, TAK-901 sensitizes cancer cells to BCL-xL inhibition. CONCLUSION: Polyploid cells induced by TAK-901 are vulnerable to BCL-xL inhibition. Our findings may have an impact on combination strategies with aurora B inhibitors in clinical studies.
