TAK-901 is an investigational, multitargeted Aurora B kinase inhibitor with potential antineoplastic activity. TAK-901 potently inhibited only a few kinases other than Aurora B in intact cells, including FLT3 and FGFR2. TAK-901 inhibited cell proliferation with effective concentration values from 40 to 500 nmol/L in various human cancer cell lines. TAK-901 suppressed cellular histone H3 phosphorylation and induced polyploidy. TAK-901 displayed potent activity against several leukemia models. 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. In vivo studies showed that TAK-901 induced pharmacodynamic responses consistent with Aurora B inhibition and correlating with retention of TAK-901 in tumor tissue. TAK-901 is currently in a phase I clinical trials in patients within a diverse range of cancers.
|Source||Anticancer Res (2017). Figure 1. TAK-901|
|Cell Lines||HCT116 cells|
|Incubation Time||72 h|
|Results||Induction of polyploidy was also detected by FACS analysis; 2N and 4N cells were observed in DMSO-treated HCT116 cells, while mainly 4N and 8N were observed in TAK-901- or AZD1152-HQPA-treated HCT116 cells|
|Cell lines||A2780, A375, A549, COLO-205, HCT116, PC-3 cells line|
|Preparation method||Cell proliferation and viability assays.
Cells were plated in 96-well microtiter plates and incubated with serial dilutions of TAK-901 for 72 hours. Cell proliferation was determined by ELISA analysis of bromodeoxyuridine (BrdUrd) incorporation into DNA (Roche Diagnostics). IMR-90 immortalized lung fibroblasts were seeded in 96-well microtiter plates and cultured for 3 to 4 days until confluent. Cells were then incubated with serial dilutions of TAK-901 for 72 hours. The MTS assay was conducted as per the manufacturer's instructions (Promega). The concentration of TAK-901 required to inhibit half of the maximal effective concentration (EC50) was determined from the dose–response curves.
|Incubation time||72 h|
|Animal models||Nude mice or rats Xenograft models|
|Formulation||12% Captisol, 25 mmol/L citrate, pH 3.0|
|Dosages||5 μL/mg twice daily|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 90 mg/mL|
Biological characterization of TAK-901, an investigational, novel, multitargeted Aurora B kinase inhibitor.
Farrell P, et al. Mol Cancer Ther. 2013 Apr;12(4):460-70. PMID: 23358665.
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PHA-680632 is potent inhibitor of Aurora A, Aurora B and Aurora C with IC50 of 27 nM, 135 nM and 120 nM, respectively. It has 10- to 200-fold higher IC50 for FGFR1, FLT3, LCK, PLK1, STLK2, and VEGFR2/3.
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PF-03814735 is a novel, potent and reversible inhibitor of Aurora A/B with IC50of 0.8 nM/5 nM, is less potent to Flt3, FAK, TrkA, and minimally active to Met and FGFR1.
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