AT9283 is a potent inhibitor of several protein kinases, including Aurora A, Aurora B, Janus kinase 2 (JAK2), JAK3, and ABL. AT9283 potently inhibited proliferation and Jak2-related signalling in Jak2-dependent cell lines. The compound also demonstrated significant therapeutic potential in vivo in an ETV6-JAK2 (TEL-JAK2) murine leukaemia model.
|Cell lines||HCT 116 cells|
|Preparation method||Primary HCT116 Cellular Assay. HCT 116 cells were cultured in DMEM + 10% FBS + GLUTAMAX I. Black 96-well flat bottomed (clear) tissue culture treated plates were seeded at 5 × 103 cells per well in 200 µL of medium and incubated for approximately 16 h at 37 °C in a humidified atmosphere of 5% CO2 in air. Cells were treated with test compound at nine different concentrations (spanning 1 nM to 10 µM, plus DMSO vehicle control) and then incubated for 72 h. Polyploidy morphological observations of the cells were then noted. The concentration of test compound required to produce a distinct polyploid phenotype was reported.|
|Concentrations||1 nM to 10 µM|
|Incubation time||72 h|
|Animal models||HCT116 Colon Carcinoma Cell Line Xenograft Model|
|Formulation||10% DMSO, 20% water, 70% hydroxypropyl--cyclodextrin (25% w/v aq)|
|Dosages||15 and 20mg/kg twice daily (b.i.d. × 2, q4d) × 5|
|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.
A phase I dose escalation study of AT9283, a small molecule inhibitor of aurora kinases, in patients with advanced solid malignancies.
Arkenau et al. Ann Oncol. 2012 May;23(5):1307-13. PMID: 22015452.
AT9283, a novel aurora kinase inhibitor, suppresses tumor growth in aggressive B-cell lymphomas.
Qi W et al. Int J Cancer. 2012 Jun 15;130(12):2997-3005. PMID: 21796626.
AT-9283, a small-molecule multi-targeted kinase inhibitor for the potential treatment of cancer.
Kimura S Curr Opin Investig Drugs. 2010 Dec;11(12):1442-9. PMID: 21154126.
AT9283, a potent inhibitor of the Aurora kinases and Jak2, has therapeutic potential in myeloproliferative disorders.
Dawson et al. Br J Haematol. 2010 Jul;150(1):46-57. PMID: 20507304.
|Related Aurora Kinase Products|
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.
GSK1070916 is a reversible and ATP-competitive inhibitor of Aurora B/C with IC50 of 3.5 nM/6.5 nM. It displays >100-fold selectivity against the closely related Aurora A-TPX2 complex.
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.
MK-5108 (VX-689) is a highly selective Aurora A inhibitor with IC50 of 0.064 nM and is 220- and 190-fold more selective for Aurora A than Aurora B/C, while it inhibits TrkA with less than 100-fold selectivity.
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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