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Purity: ≥98%
AT9283 is a novel, potent and selective inhibitor of multikinase including Aurora A/B, JAK2/3, Abl (T315I) and Flt3 etc. It was identified from fragment-based approach as a potential antineoplastic agent for the treatment of multiple myeloma. AT9283 inhibits JAK2/3 with IC50s of 1.2 nM/1.1 nM in cell-free assays. AT9283 binds to and inhibits Aurora kinases A and B, JAK2 and the kinase BCR-ABL, which may result in the inhibition of cellular division and proliferation and the induction of apoptosis in tumor cells that overexpress these kinases.
| ln Vitro |
AT9283 inhibits Aurora B kinase activity in HCT116 cells with an IC50 of 30 nM, resulting in a phenotypic that is obviously polyploid. Additionally, AT9283 inhibits HCT116 colony development with a strong degree[1]. AT9283 reduces cell proliferation with an IC50 < 1 μM in B-NHL cell lines and promotes apoptosis in a dose- and time-dependent manner[2]. In MM cell lines, AT9283 inhibits the STAT3 signaling pathway, causes dose-dependent cytotoxicity, and hinders proliferation. T9283 suppresses the phosphorylation of Histone H3 and Aurora A at Thr 288. Time-dependently, AT9283 causes MM cells to enter the G2/M phase and undergo apoptosis[3].
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| ln Vivo |
Treatment with AT9283 (15 mg/kg and 20 mg/kg) for 16 days causes a considerable tumor growth inhibition of 67% and 76%, respectively, in mice bearing HCT116 human colon cancer xenografts. Furthermore, compared to plasma, AT9283 has a much longer half-life in tumors (2.5 hours) and a moderate oral bioavailability in mice[1]. The combined anti-tumor efficacy of docetaxel (10 mg/kg) and AT9283 (15 mg/kg) is moderate. In a mouse xenograft model of mantle cell lymphoma, T9283 at 20 mg/kg and AT9283 (15 or 20 mg/kg) plus docetaxel (10 mg/kg) show a statistically significant tumor growth suppression and improve survival[2]. In mice, AT9283 (45 mg/kg, ip) suppresses the formation of tumors. Reduced expression of phospho-Histone H3 and Aurora B in treated rats is confirmed by two cycles of AT9283 45 mg/kg administered 14 hours after medication administration[3].
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| References |
[1]. Howard S, et al. Fragment-Based Discovery of the Pyrazol-4-yl Urea (AT9283), a Multitargeted Kinase Inhibitor with Potent Aurora Kinase Activity. Journal of Medicinal Chemistry (2009), 52(2), 379-388.
[2]. Qi W, et al. AT9283, a novel aurora kinase inhibitor, suppresses tumor growth in aggressive B-cell lymphomas. Int J Cancer. 2012 Jun 15;130(12):2997-3005. [3]. Santo L, et al. Antimyeloma activity of a multitargeted kinase inhibitor, AT9283, via potent Aurora kinase and STAT3 inhibition either alone or in combination with lenalidomide. Clin Cancer Res. 2011 May 15;17(10):3259-71 |
| Molecular Formula |
C19H23N7O2
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|---|---|
| Molecular Weight |
381.43
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| CAS # |
896466-04-9
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| Related CAS # |
AT9283 lactic acid;896466-76-5
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| SMILES |
O=C(NC1=CNN=C1C2=NC3=CC(CN4CCOCC4)=CC=C3N2)NC5CC5
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| InChi Key |
LOLPPWBBNUVNQZ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H23N7O2/c27-19(21-13-2-3-13)24-16-10-20-25-17(16)18-22-14-4-1-12(9-15(14)23-18)11-26-5-7-28-8-6-26/h1,4,9-10,13H,2-3,5-8,11H2,(H,20,25)(H,22,23)(H2,21,24,27)
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| Chemical Name |
1-cyclopropyl-3-(3-(5-(morpholinomethyl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazol-4-yl)urea
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| Synonyms |
AT9 283; AT-9283; AT9283
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6217 mL | 13.1086 mL | 26.2171 mL | |
| 5 mM | 0.5243 mL | 2.6217 mL | 5.2434 mL | |
| 10 mM | 0.2622 mL | 1.3109 mL | 2.6217 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01145989 | Completed | Drug: AT9283 | Multiple Myeloma | NCIC Clinical Trials Group | February 15, 2011 | Phase 2 |
| NCT00443976 | Completed | Drug: Aurora kinase inhibitor AT9283/td> | Non-Hodgkins Lymphoma Unspecified Adult Solid Tumor, Protocol Specific |
NCIC Clinical Trials Group | January 30, 2007 | Phase 1 |
| NCT00522990 | Terminated | Drug: AT9283 | Acute Myeloid Leukemia Acute Lymphoblastic Leukemia |
Astex Pharmaceuticals, Inc. | September 2006 | Phase 1 Phase 2 |
| NCT01431664 | Completed | Drug: multikinase inhibitor AT9283 Other: laboratory biomarker analysis |
Leukemia | Cancer Research UK | September 2011 | Phase 1 |
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