3-cyclopropyl-1-{3-[5-(morpholin-4-ylmethyl)-1H-1,3-benzodiazol-2-yl]-1H-pyrazol-4-yl}urea

• ChemBase编号: 72532
• 分子式: C19H23N7O2
• 平均质量: 381.43162
• 单一同位素质量: 381.19132301
• SMILES: N(C(=O)Nc1c(n[nH]c1)c1[nH]c2c(n1)cc(cc2)CN1CCOCC1)C1CC1
• Canonical SMILES: O=C(Nc1c[nH]nc1c1nc2c([nH]1)ccc(c2)CN1CCOCC1)NC1CC1
• 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)
• InChIKey: LOLPPWBBNUVNQZ-UHFFFAOYSA-N

名称和登记号

名称

• IUPAC标准名: 3-cyclopropyl-1-{3-[5-(morpholin-4-ylmethyl)-1H-1,3-benzodiazol-2-yl]-1H-pyrazol-4-yl}urea
• IUPAC传统名: 3-cyclopropyl-1-{3-[5-(morpholin-4-ylmethyl)-1H-1,3-benzodiazol-2-yl]-1H-pyrazol-4-yl}urea
• 别名: AT9283

登记号

• CAS号: 896466-04-9
• PubChem SID: 162037457
• PubChem CID: 11696609

理论计算性质

• Acid pKa: 9.879882
• 质子受体: 5
• 质子供体: 4
• LogD (pH = 5.5): -0.11786513
• LogD (pH = 7.4): 1.1723673
• Log P: 1.2906103
• 摩尔折射率: 116.6503 cm^3
• 极化性: 41.398808 Å^3
• 极化表面积: 110.96 Å^2
• 可自由旋转的化学键: 5
• 里宾斯基五规则: true

分子性质

理化性质

• 溶解度: DMSO

安全信息

• 保存条件: -20°C

药理学性质

• 作用靶点: Aurora Kinase; Bcr-Abl; JAK

产品相关信息

• 成盐信息: Free Base

详细说明

Selleck Chemicals - S1134

Research Area

• Description: Solid tumours, Haematological malignancies

Biological Activity

• Description: AT9283 is a potent pan-Aurora inhibitor for Aurora A, Aurora B, JAK3, JAK2 and Abl with IC50 of 3 nM, 3 nM, 1.1 nM, 1.2 nM and 4 nM, respectively.
• Targets:

  Aurora A

  ;

  Aurora B

  ;

  JAK3

  ;

  JAK2

  ;

  Abl

• IC50:

  3 nM

  ;

  3 nM

  ;

  1.1 nM

  ;

  1.2 nM

  ;

  4 nM ^[1]

• In Vitro: AT9283 leads to a clear polyploid phenotype by inhibiting the activity of Aurora B kinase in HCT116 cells with IC50 of 30 nM. Furthermore, AT9283 also produces the potent inhibition on HCT116 colony formation. ^[1]
• 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 (Fp.o. = 24%). ^[1]
• Clinical Trials: AT9283 is currently in Phase I clinical trials in patients with Advanced or Metastatic Solid Tumors or Non-Hodgkin's Lymphoma.

Combination Therapy

• Description:

  A recent study shows that the combination treatment of AT9283 (15 nM) and imatinib (2 μM) produces more potent effects in increasing apoptosis and reduced cell proliferation than either drug treatment alone. ^[2] In a mouse xenograft model of mantle cell lymphoma, combination treatment of AT9283 (15 mg/kg or 20 mg/kg) and docetaxel (10 mg/kg) leads to a statistically significant tumor growth inhibition than AT9283 (15 mg/kg) and docetaxel (10 mg/kg) alone. ^[3]

Protocol

• Protocol: Kinase Assay ^[1]
• Aurora A and Aurora B Kinase Assays: Assays for Aurora A and B are performed in a DELFIA format. Aurora A enzyme is incubated with AT9283 and 3 μM cross-tide substrate (biotin-CGPKGPGRRGRRRTSSFAEG) in 10 mM MOPS, pH 7, 0.1 mg/mL BSA, 0.001% Brij-35, 0.5% glycerol, 0.2 mM EDTA, 10 mM MgCl₂, 0.01% β-mercaptoethanol, 15 μM ATP, and 2.5% DMSO. Aurora B enzyme is incubated with AT9283, 3 μM of the above substrate in 25 mM Tris, pH 8.5, 5 mM MgCl₂, 0.1 mg/mL BSA, 0.025% Tween-20, 1 mM DTT, 15 μM ATP, and 2.5% DMSO. Reactions are allowed to proceed for 60 minutes and 45-90 minutes for Aurora A and Aurora B, respectively, before quenching with EDTA. The reaction mixtures are then transferred to a neutravidin-coated plate, and phosphorylated peptide is quantified by means of a phospho-specific antibody and a europium labeled secondary antibody using time-resolved fluorescence (excitation, 337 nm; emission, 620 nm). IC50 values for the control compounds are 92 nM (Aurora A assay) and 17 nM (Aurora B).
• Protocol: Cell Assay ^[1]
• Cell Lines: HCT 116 cells
• Concentrations: 1 nM - 10 μM
• Incubation Time: 72 hours
• Methods:

  HCT 116 cells are cultured in DMEM + 10% FBS + GLUTAMAX I. Black 96-well flat-bottomed (clear) tissue culture treated plates are seeded in 200 μL of medium and incubated for approximately 16 hours at 37°C in a humidified atmosphere of 5% CO₂ in air. Cells are treated with test compound at nine different concentrations (spanning 1 nM to 10 μM, plus DMSO vehicle control) and then incubated for 72 hours. Polyploidy morphological observations of the cells are then noted. The concentration of AT9283 required to produce a distinct polyploid phenotype is reported. Cells are seeded at a concentration of 75−100 cells/mL relevant culture media onto 6- or 24-well tissue culture plates and allowed to recover for 16 hours. Test compound (11 concentrations spanning 0.1 nM to 10 μM) or vehicle control (DMSO) is added to duplicate wells to give a final DMSO concentration of 0.1%. Following compound addition, colonies are allowed to grow between 10 and 14 days for optimum discrete colony counting. Colonies are fixed in 2 mL of Carnoys fixative (25% acetic acid, 75% MeOH) and stained in 2 mL of 0.4% w/v crystal violet. The numbers of colonies in each well is counted. IC50 values are calculated by sigmoidal dose-response (variable slope) IC50 curves using Prism Graphpad software.

• Protocol: Animal Study ^[1]
• Animal Models: HCT116 cells are injected s.c. Into the hind flank of male BALB/c mice.
• Formulation: Belinostat is dissolved in 10% DMSO, 20% water, 70% hydroxypropyl- β-cyclodextrin (25% w/v aq).
• Doses: 15 mg/kg and 20 mg/kg
• Administration: Administered via i.p.

References

• References: [1] Howard S, et al. J Med Chem, 2009, 52(2), 379-388.

参考文献

• Howard S, et al. J Med Chem, 2009, 52(2), 379-388.