GSK1070916 is a novel, highly potent and selective Aurora B/C kinases ATP competitive inhibitor with an EC50 of <10 nM. The protein kinases, Aurora A, B, and C have critical roles in the modulation of mitosis and are frequently overexpressed or amplified in human tumors. Human tumor cells treated with GSK1070916 revealed dose-dependent inhibition of phosphorylation on serine 10 of Histone H3, a substrate specific for Aurora B kinase. Moreover, GSK1070916 supprresses the proliferation of tumor cells. GSK1070916 displays dose-dependent inhibition of phosphorylation of an Aurora B–specific substrate in mice and consistent with its broad cellular activity, possesses antitumor effects in 10 human tumor xenograft models including breast, colon, lung, and two leukemia models. In another study, GSK1070916 selectively prevents AurB-INCENP (Ki=0.38 nM) and AurC-INCENP (Ki=1.5 nM) over AurA-TPX2 (target protein for Xenopus kinesin-like protein 2) (Ki=490 nM). Suppression of AurB-INCENP and AurC-INCENP is time-dependent, with an enzyme-inhibitor dissociation half-life of more than 480 min and 270 min respectively.
|Cell lines||SW48, Colo 201, SW480, WiDr, Colo205, RKO E6, RKO, LoVo, HCT-116, SW620, HT29, W1417, DLD-1, HCT-8, Colo 320HSR, Hep-3B, OVCAR-3, MEC-1 cells|
|Preparation method||Plating cells in 96-well plates in the recommended growth media and incubated at 37 °C in 5% CO2 overnight. The following day, treating the cells with serial dilutions of GSK1070916. At this time, treating one set of cells with CellTiter-Glo for a time equal to 0 (T = 0) measurement. Following a 6- to 7-d incubation with compound, using the CellTiter-Glo reagent to measure cell proliferation according to the manufacture's recommended protocol. As inhibition of Aurora B induces endomitosis, the degree of which differs depending on the cell type, an extended compound treatment time is required to accurately reflect the effects on cell viability across a large panel of cell lines. For analysis of cell viability, values from wells with no cells are subtracted for background correction and the data plotted as a percent of the DMSO-treated control samples using Microsoft Excel XLfit4 software. The EC50 values represent the concentration of GSK1070916 where 50% maximal effect is observed|
|Incubation time||6-7 days|
|Animal models||Mice tumor xenograft models (A549, SW620, HCT116, H460, MCF-7, HL60, K562, Colo205)|
|Formulation||2% Cremophor EL, 2% N,N-dimethylacetamide, and 96% acidified water (pH 5.0)|
|Dosages||25, 50, or 100 mg/kg|
|Administration||Administered via i.p. once 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 Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
|Solubility||DMSO 100 mg/mL|
|Related Aurora Kinase Products|
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SNS-314 is a potent and selective inhibitor of Aurora A, Aurora B and Aurora C with IC50 of 9 nM, 31 nM, and 3 nM, respectively and less potent to Trk A/B, Flt4, Fms, Axl, c-Raf and DDR2.
|Aurora Kinase Inhibitor III
Aurora Kinase Inhibitor III is a strong and selective Aurora A kinase inhibitor with an IC50 of 42 nM.
SNS-314 Mesylate is a potent and selective inhibitor of Aurora A, Aurora B and Aurora C with IC50 of 9 nM, 31 nM, and 3 nM, respectively.
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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