| Identification | Back Directory | [Name]
AT9283 | [CAS]
896466-04-9 | [Synonyms]
CS-48
J-504568
AT9283, >=98%
AT-9283; AT 9283
N-cyclopropyl-N'-[3-[5-(4-morpholinylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]Urea
1-Cyclopropyl-3-(3-(5-(morpholinomethyl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazol-4-yl)urea
Urea, N-cyclopropyl-N'-[3-[6-(4-morpholinylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]-
1-Cyclopropyl-3-(3-(5-(morpholinomethyl)-1H-benzo[d]imidazol-2-yl)-1H-pyrazol-4-yl)urea AT9283 | [Molecular Formula]
C19H23N7O2 | [MDL Number]
MFCD12031513 | [MOL File]
896466-04-9.mol | [Molecular Weight]
381.438 |
| Chemical Properties | Back Directory | [density ]
1.45 | [storage temp. ]
Keep in dark place,Inert atmosphere,2-8°C | [solubility ]
insoluble in H2O; ≥19.05 mg/mL in DMSO; ≥47.6 mg/mL in EtOH with ultrasonic | [form ]
solid | [pka]
10.58±0.10(Predicted) | [color ]
White to off-white |
| Hazard Information | Back Directory | [Uses]
AT-9283 is a broad spectrum kinase inhibitor that potently inhibits Aurora A, Aurora B, JAK2, JAK3, and c-ABL (IC50s = 3, 3, 1.2, 1.1, and 4 nM, respectively). It also potently (IC50 = <1 μM) inhibits many other kinases, including serine/threonine kinases as well as receptor and non-receptor tyrosine kinases. As Aurora kinases have roles in mitosis, inhibitors of these kinases, including AT-9283, have potential in cancer therapy. Consistent with this, AT-9283 is effective in preventing proliferation of cancer cells both in vitro and in vivo and this effect may be enhanced by combination therapy with other chemotherapeutics.[Cayman Chemical] | [Definition]
ChEBI:1-cyclopropyl-3-[3-[5-(4-morpholinylmethyl)-2-benzimidazolylidene]-1,2-dihydropyrazol-4-yl]urea is a member of benzimidazoles. | [Biological Activity]
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.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. | [Synthesis]
7-Morpholin-4-ylmethyl-2,5,4-dihydro-1,2,4,5a,10-pentaaza-cyclopenta[a]fluoren-5-one (0.797 kg, 2.46 mol, 1.0 eq.) and 1-methyl-2-pyrrolidinone (2.40 L, 3.0 v/v) were added slowly to a flanged flask equipped with a mechanical stirrer, a condenser and a thermometer in a flammable atmosphere protected by nitrogen at 15 to 30 °C. The mixture of cyclopropylamine (0.279 kg, 4.88 mol, 0.35 eq.) and 1-methyl-2-pyrrolidone (2.40 L, 3.0 v/v) were added slowly at 15 to 30 °C under nitrogen. Cyclopropylamine (0.279 kg, 4.88 mol, 0.35 eq.) was slowly added at 15 to 30 °C under the protection of nitrogen. The reaction mixture was heated to 95 to 105 °C and stirred at this temperature for 16 to 24 h. The completion of the reaction was monitored by 1H NMR. Upon completion of the reaction, the mixture was cooled to 10 to 20 °C, ethyl acetate (8.00 L, 10.0 v/v) and saturated NaHCO3 aqueous solution (2.50 L, 3.0 v/v) were added, and the mixture was stirred for 2 to 5 minutes and then partitioned. The organic phase was washed with saturated aqueous NaHCO3 (5.00 L, 1.0 volume) for 25 to 35 minutes, filtered and the filter cake was washed with ethyl acetate (0.40 L, 0.5 volume). The filter cake was retained and the filtrate was transferred to a partitioning funnel for layering and the process was repeated three times. The retained solid was combined with the organic phase and the mixture was concentrated to dryness under vacuum at 35 to 45 °C. The concentrate was dissolved in isopropanol (8.00 L, 10.0 v/v) at 45 to 55 °C, activated charcoal (0.080 kg, 0.1 eq.) was added, and the mixture was stirred at 45 to 55 °C for 30 to 40 min and then hot-filtered, and the filter cake was washed with isopropanol (0.40 L, 0.5 v/v). Activated carbon (0.080 kg, 0.1 equiv) was added to the combined filtrates and the mixture was stirred at 45 to 55 °C for 30 to 40 minutes before hot filtration and the filter cake was washed with isopropanol (0.40 L, 0.5 v/v). The filtrate and washings were concentrated under vacuum at 35 to 45 °C. To the concentrate was added ethyl acetate (8.00 L, 10.0 v/v) and water (2.20 L, 3.0 v/v), the mixture was stirred for 1 to 2 minutes at 25°C and then partitioned, and the organic phase was concentrated under vacuum at 35 to 45°C. Ethyl acetate (4.00 L, 5.0 vol) was added to the residue and the mixture was concentrated under vacuum at 35 to 45 °C. After repeating this operation once, the residue was stirred at 15 to 25°C for 2 to 20 hours, cooled to 0°C and aged at 0 to 5°C for 90 to 120 minutes before being filtered. The filter cake was washed with ethyl acetate (0.80 L, 1.0 v/v), dried for 15 to 30 min, and the solid was dried under vacuum at 35 to 45 °C to afford the target product 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]urea (0.533 kg, 56.8% yield, 93.20% HPLC purity) as a brown solid. ), a brown solid. | [Enzyme inhibitor]
This potent JAK protein kinase inhibitor (FW = 381.43 g/mol; CAS
896466-04-9; Solubility = 76 mg/mL DMSO), also named 1-cyclopropyl-
3- (3- (5- (morpholinomethyl) -1H-benzo[d]imidazol-2-yl) -1H-pyrazol-4-
yl) urea, targets JAK3 (IC50 = 1.1 nM), JAK2 (IC50 = 1.2 nM), Aurora A
(IC50 = 3 nM), Aurora B (IC50 = 3 nM), and and Abl (T315I). | [in vivo]
In HCT116 human colon carcinoma xenograft bearing mice, AT9283 treatment (15 mg/kg and 20 mg/kg) for 16 days results in a significant tumor growth inhibition of 67% and 76%, respectively. In addition, AT9283 also exhibits a significantly longer half-life in tumors (2.5 hours) compared with plasma (0.5 hour) and modest oral bioavailability in mice[1].
AT9283 (15 mg/kg) and docetaxel (10 mg/kg) alone has modest anti-tumor activity. T9283 at 20 mg/kg and AT9283 (15 or 20 mg/kg) plus docetaxel (10 mg/kg) demonstrate a statistically significant tumor growth inhibition and enhance survival inmouse xenograft model of mantle cell lymphoma[2].
AT9283 (45 mg/kg, i.p.) inhibits tumor growth in mice. Two cycles of AT9283 45 mg/kg 14 hours after drug administration confirm decreased expression of phospho-Histone H3 and Aurora B in treated animals[3]. | [target]
Aurora A | [IC 50]
Aurora A: 3 nM (IC50); Aurora B: 3 nM (IC50); JAK3: 1.1 nM (IC50); JAK2: 1.2 nM (IC50); ABL(T315I): 4 nM (IC50); Flt-3 | [storage]
Store at -20°C | [References]
[1] Patent: WO2006/70195, 2006, A1. Location in patent: Page/Page column 193-194
[2] Patent: WO2007/77435, 2007, A1. Location in patent: Page/Page column 247-248
[3] Patent: WO2008/1101, 2008, A2. Location in patent: Page/Page column 294; 301-303; 306-308
[4] Patent: WO2008/1101, 2008, A2. Location in patent: Page/Page column 305 |
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