CAS NO: | 934541-31-8 |
规格: | ≥98% |
包装 | 价格(元) |
25mg | 电议 |
50mg | 电议 |
100mg | 电议 |
250mg | 电议 |
500mg | 电议 |
Molecular Weight (MW) | 504.64 |
---|---|
Formula | C28H32N4O3S |
CAS No. | 934541-31-8 |
Storage | -20℃ for 3 years in powder form |
-80℃ for 2 years in solvent | |
Solubility (In vitro) | DMSO: 101 mg/mL (200.1 mM) |
Water: <1 mg/mL | |
Ethanol: <1 mg/mL | |
Other info | Chemical Name: 5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide InChi Key: WKDACQVEJIVHMZ-UHFFFAOYSA-N InChi Code: 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) SMILES Code: O=C(C1=C(C)C2=C(C(C3=CC=CC(S(=O)(CC)=O)=C3)=C1)C4=CC(C)=CN=C4N2)NC5CCN(C)CC5 |
Synonyms | TAK-901, TAK 901, TAK901 |
In Vitro | In vitro activity: TAK-901 inhibits Aurora A-TPX2 and Aurora B-INCENP in tight binding, time-dependent manner. Dissociation of TAK-901 from Aurora B-INCENP is slow with at 1/2 of 920 minutes, and the affinity constant for TAK-901 binding to Aurora B-INCENP is determined to be 0.02 nM. TAK-901 induces inhibition of cell proliferation in cultured human cancer cell lines from different tissues with IC50s ranging from 40 to 500nM. Consistent with Aurora B inhibition, TAK-901 treatment produces polyploidy in human PC3 prostate cancer and HL60 acute myeloid leukemia cells as measured by immunofluorescence and flow cytometry. Examination of a broad panel of kinases reveals that multiple kinases, including FLT3, FGFR and the Src family kinases, are inhibited by TAK-901 with IC50 values similar to those for Aurora A and B. In cells, TAK-901 suppresses the Flt3 and FGFR2 autophosphorylation with IC50 values close to that of Aurora B as measured by cellular histone H3 phosphorylation, whereas the IC50s for inhibition of cellular Src and Bcr Abl are 20-fold weaker. In a panel of pathway specific reporter-based cell models, TAK-901 inhibits the NFkB and JAK/STAT pathways with submicromolar potency. Kinase Assay: TAK-901 is a novel inhibitor of Aurora A/B with IC50 of 21 nM/15 NM. TAK-901 inhibits Aurora A-TPX2 and Aurora B-INCENP in tight binding, time-dependent manner. Dissociation of TAK-901 from Aurora B-INCENP is slow with at 1/2 of 920 minutes, and the affinity constant for TAK-901 binding to Aurora B-INCENP is determined to be 0.02 NM. Cell Assay: TAK-901 induces inhibition of cell proliferation in cultured human cancer cell lines from different tissues with IC50s ranging from 40 to 500nM. Consistent with Aurora B inhibition, TAK-901 treatment produces polyploidy in human PC3 prostate cancer and HL60 acute myeloid leukemia cells as measured by immunofluorescence and flow cytometry. Examination of a broad panel of kinases reveals that multiple kinases, including FLT3, FGFR and the Src family kinases, are inhibited by TAK-901 with IC50 values similar to those for Aurora A and B. In cells, TAK-901 suppresses the Flt3 and FGFR2 autophosphorylation with IC50 values close to that of Aurora B as measured by cellular histone H3 phosphorylation, whereas the IC50s for inhibition of cellular Src and Bcr Abl are 20-fold weaker. In a panel of pathway specific reporter-based cell models, TAK-901 inhibits the NFkB and JAK/STAT pathways with submicromolar potency. |
---|---|
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 |
Animal model | Mice and rats |
Formulation & Dosage | Intravenously twice daily (b.i.d.) |
References | Mol Cancer Ther. 2013 Apr;12(4):460-70. |
A, chemical structure of TAK-901. B, TAK-901 inhibition of Aurora A and B kinase/coactivator complexes and kinetic data of the Aurora B/INCENP enzyme complex. C, kinase inhibition profile of TAK-901. D, enzyme reaction progression curves showing TAK-901 time-dependent binding to (D) and dissociation (E) from Aurora B/INCENP enzyme complex. Mol Cancer Ther. 2013 Apr;12(4):460-70. | TAK-901 inactivates cellular Aurora B kinase and inhibits cell proliferation. A, immunoblot analysis of histone H3 phosphorylation in PC3 cells treated with TAK-901. B, PC3 cells were incubated for 48 hours with dimethyl sulfoxide or 0.2 μmol/L TAK-901 and stained for actin (green) and DNA (blue). C, DNA content histograms of HL60 cells after incubation for 48 hours with a concentration dilution series of TAK-901. D, TAK-901 EC50 values for cell proliferation (DNA synthesis) inhibition in cells. Mol Cancer Ther. 2013 Apr;12(4):460-70. | Profile of various TAK-901 kinase targets. A, MV4-11 cells, 2 μmol/L FLT3/MTK inhibitor. B, KATO-III cells, 10 μmol/L Aurora B inhibitor. C, profile of TAK-901 cellular activity against Aurora B kinase and several cross-reacting kinases. EC50 values derived from dose–response immunoblotting or cellular reporter. Mol Cancer Ther. 2013 Apr;12(4):460-70. |
In vivo antitumor activity of TAK-901 in human tumor and leukemia xenograft models. Mol Cancer Ther. 2013 Apr;12(4):460-70. | In vivo effects of TAK-901 on Aurora B pharmacodynamic markers. A, histone H3 phosphorylation in nude rat A2780 xenograft tumors. B, polyploidy in nude mice A2780 xenograft tumors. Mol Cancer Ther. 2013 Apr;12(4):460-70. |