AT9283Aurora kinase/JAK inhibitor CAS# 896466-04-9 |
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Quality Control & MSDS
Number of papers citing our products
Chemical structure
3D structure
| Cas No. | 896466-04-9 | SDF | Download SDF |
| PubChem ID | 135398495 | Appearance | Powder |
| Formula | C19H23N7O2 | M.Wt | 381.43 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : ≥ 100 mg/mL (262.17 mM) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | 1-cyclopropyl-3-[5-[6-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]urea | ||
| SMILES | C1CC1NC(=O)NC2=C(NN=C2)C3=NC4=C(N3)C=C(C=C4)CN5CCOCC5 | ||
| Standard InChIKey | LOLPPWBBNUVNQZ-UHFFFAOYSA-N | ||
| Standard InChI | 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) | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | AT9283 is a potent inhibitor of Aurora with IC50 values of 3 nM, 3 nM, 1.1 nM, 1.2 nM and 4 nM for Aurora A, Aurora B, JAK3, JAK2 and c-Abl, respectively. | ||||||
| Targets | Aurora A | Aurora B | JAK3 | JAK2 | c-Abl | ||
| IC50 | 3 nM | 3 nM | 1.1 nM | 1.2 nM | 4 nM | ||
AT9283 Dilution Calculator
AT9283 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.6217 mL | 13.1086 mL | 26.2171 mL | 52.4343 mL | 65.5428 mL |
| 5 mM | 0.5243 mL | 2.6217 mL | 5.2434 mL | 10.4869 mL | 13.1086 mL |
| 10 mM | 0.2622 mL | 1.3109 mL | 2.6217 mL | 5.2434 mL | 6.5543 mL |
| 50 mM | 0.0524 mL | 0.2622 mL | 0.5243 mL | 1.0487 mL | 1.3109 mL |
| 100 mM | 0.0262 mL | 0.1311 mL | 0.2622 mL | 0.5243 mL | 0.6554 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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AT9283, a synthetic small heterocyclic molecule discovered using a fragment-based approach, is a novel inhibitor of aurora kinase, a family of serine/threonine kinases regulating both mitosis and meiosis, that potently inhibits Aurora kinases A and B, with 50% inhibition concentration IC50 value of 3 nM, as well as Janus kinases (JAKs), Abelson kinase (BCRABL T315I) and Flt-3. AT9283 has been found to be therapeutic in leukemic cells, myeloproliferative disorders and multiple solid tumor cell lines. Study results have shown that AT9283 exhibits anti-proliferative activity and induces polyploidy and apoptosis in aggressive B-cell NHL cell lines associated with inhibition of Aurora kinase B.
Reference
Qi W, Liu X, Cooke LS, Persky DO, Miller TP, Squires M, Mahadevan D. AT9283, a novel aurora kinase inhibitor, suppresses tumor growth in aggressive B-cell lymphomas. Int J Cancer. 2012 Jun 15;130(12):2997-3005. doi: 10.1002/ijc.26324. Epub 2011 Nov 19.
Arkenau HT, Plummer R, Molife LR, Olmos D, Yap TA, Squires M, Lewis S, Lock V, Yule M, Lyons J, Calvert H, Judson I. A phase I dose escalation study of AT9283, a small molecule inhibitor of aurora kinases, in patients with advanced solid malignancies. Ann Oncol. 2012 May;23(5):1307-13. doi: 10.1093/annonc/mdr451. Epub 2011 Oct 19.
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Optimizing and predicting the in vivo activity of AT9283 as a monotherapy and in combination with paclitaxel.[Pubmed:26346504]
J Gastrointest Cancer. 2015 Dec;46(4):380-9.
OBJECTIVES: This study aims in optimizing and predicting the in-vivo activity of AT9283 as a monotherapy and evaluating its combination with paclitaxel. DESIGN AND METHODS: The effectiveness of AT9283 was examined in several mouse models engrafted with BCR-ABL(+) leukemic, human multiple myeloma (MM), and human colorectal carcinoma (HCT116) cells. Dose modeling was performed by analyzing previously published data of AT9283 cancer growth inhibition in vivo. The effects of 2 cycles (7.5-12.5 mg/kg AT9283 twice daily, 5 days/week), 4 cycles (45 mg/kg AT9283 once daily, twice/week), and 3 cycles (10 mg/kg AT9283 twice daily for 5 days or 12.5 mg/kg paclitaxel once/week followed by 5 mg/kg AT9283 twice daily for 4 days) on xenograft growth were quantified to identify the energy yield associated with the different doses. RESULTS: The continuous infusion regimens (5 days/week) used in the mice engrafted with BCR-ABL+ cells were more efficient than the regimens with twice weekly drug administration used in the mice engrafted with MM cells. The energy yield of the treatment regimen used in the BCR-ABL(+) model was perfectly correlated (r = 1) with the AT9283 dose logarithm. An efficient dose-energy model with a perfect fit (R (2) = 1) estimating the energy yield achieved by the different AT9283 doses in optimal regimens was established with the aim of being able to administer patient-specific AT9283 doses. In the HCT116 model, the predicted response to AT9283 monotherapy was nearly identical to the actual response. The regimen combining paclitaxel (1050 mg/L) with low-dose AT9283 (3360 mg/L) used in the HCT116 model was equivalent to an optimal regimen of a higher dose of AT9283 (11,332 mg/L) alone. CONCLUSIONS: Administering AT9283 via continuous infusion optimizes treatment, while combining it with paclitaxel significantly reduces the required AT9283 dose for the advanced-stage tumors with low mitotic index.
A population pharmacokinetic model of AT9283 in adults and children to predict the maximum tolerated dose in children with leukaemia.[Pubmed:28177130]
Br J Clin Pharmacol. 2017 Aug;83(8):1713-1722.
AIMS: AT9283 is used to treat patients with solid tumours and patients with leukaemia. However, the maximum tolerated dose (MTD) for children with leukaemia remains unknown due to early termination of the Phase I trial. The aim of this study was to develop a population model of AT9283 to describe the pharmacokinetics in adults and children and to estimate the MTD in children with leukaemia. METHODS: Data from Phase I dose-escalation studies in adults and children were used to build a population pharmacokinetic model (NONMEM v7.3). Potential covariates investigated included body weight, body surface area (BSA), glomerular filtration rate (GFR), age and sex. Model-derived area under the concentration-time curve was used to investigate the relationship between dose and exposure in adults and children. RESULTS: The plasma concentrations of AT9283 (n = 1770) from 92 patients (53 adults, 39 children) were used to build a two-compartment model with all pharmacokinetic parameters scaled using body weight. Renal function (GFR), but not BSA, was a significant covariate for the clearance of AT9283. In children with leukaemia (median weight 16 kg), a flat dose of 500 mg 72 h(-1) provided similar drug exposures at the MTD as the adult population. The estimated MTD for children with leukaemia, therefore, is 30 mg kg(-1) 72 h(-1) . CONCLUSION: For adults, GFR was a significant predictor of clearance, whilst body-weight based dosing was more useful than BSA in determining the drug exposure in children. The MTD was estimated to be 30 mg kg(-1) 72 h(-1) children with leukaemia.
A phase I/II trial of AT9283, a selective inhibitor of aurora kinase in children with relapsed or refractory acute leukemia: challenges to run early phase clinical trials for children with leukemia.[Pubmed:27905678]
Pediatr Blood Cancer. 2017 Jun;64(6).
Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies.
