N-(cyanomethyl)-4-(2-{[4-(morpholin-4-yl)phenyl]amino}pyrimidin-4-yl)benzamide

• ChemBase编号: 72907
• 分子式: C23H22N6O2
• 平均质量: 414.45978
• 单一同位素质量: 414.18042397
• SMILES: c1c(ccc(c1)Nc1nccc(n1)c1ccc(cc1)C(=O)NCC#N)N1CCOCC1
• Canonical SMILES: N#CCNC(=O)c1ccc(cc1)c1ccnc(n1)Nc1ccc(cc1)N1CCOCC1
• InChI: InChI=1S/C23H22N6O2/c24-10-12-25-22(30)18-3-1-17(2-4-18)21-9-11-26-23(28-21)27-19-5-7-20(8-6-19)29-13-15-31-16-14-29/h1-9,11H,12-16H2,(H,25,30)(H,26,27,28)
• InChIKey: ZVHNDZWQTBEVRY-UHFFFAOYSA-N

名称和登记号

名称

• IUPAC标准名: N-(cyanomethyl)-4-(2-{[4-(morpholin-4-yl)phenyl]amino}pyrimidin-4-yl)benzamide
• IUPAC传统名: N-(cyanomethyl)-4-(2-{[4-(morpholin-4-yl)phenyl]amino}pyrimidin-4-yl)benzamide
• 别名: CYT 11387; Cyt-387; Cyt387

登记号

• CAS号: 1056634-68-4
• PubChem SID: 162037827
• PubChem CID: 25062766

理论计算性质

• Acid pKa: 14.019202
• 质子受体: 7
• 质子供体: 2
• LogD (pH = 5.5): 2.700519
• LogD (pH = 7.4): 2.7013047
• Log P: 2.701315
• 摩尔折射率: 118.4608 cm^3
• 极化性: 45.041218 Å^3
• 极化表面积: 103.17 Å^2
• 可自由旋转的化学键: 6
• 里宾斯基五规则: true

分子性质

安全信息

• 保存条件: -20°C

药理学性质

• 作用靶点: JAK

产品相关信息

• 成盐信息: Free Base

详细说明

Selleck Chemicals - S2219

Research Area

• Description: Myeloproliferative disorders

Biological Activity

• Description: CYT387 is an ATP-competitive inhibitor of JAK1 and JAK2 with IC50 of 11 nM and 18 nM, respectively.
• Targets: JAK1; JAK2; JAK3
• IC50: 11 nM; 18 nM; 155 nM ^[1]
• In Vitro: CYT387 inhibits the proliferation of parental Ba/F3 cells (Ba/F3-wt) stimulated by IL-3 with IC50 of 1400 nM. Furthermore, CYT387 also causes the inhibition of cell proliferation in cell lines constitutively activated by JAK2 or MPL signaling, including Ba/F3-MPLW515L cells, CHRF-288-11 cells and Ba/F3-TEL-JAK2 cells with IC50 of 200 nM, 1 nM and 700 nM, respectively. In addition, CYT387 has been shown to inhibit erythroid colony growth in vitro from JAK2V617F-positive PV patients with similar potency with IC50 of 2μ-4 μM. ^[1] A recent study shows that CYT387 inhibits PI3K/AKT and Ras/MAPK signaling induced by IL-6 and IGF-1. Moreover, CYT387 induces apoptosis as a single agent and synergizes with the conventional anti-MM therapies bortezomib and melphalan in primary multiple myeloma (MM) cells. ^[2]
• In Vivo: In a murine MPN model, CYT387 normalizes white cell counts, hematocrit, spleen size, and restores physiologic levels of inflammatory cytokines. ^[3]
• Clinical Trials: Cyt387 is currently in Phase I/II clinical trials in patients with primary myelofibrosis or post-polycythemia vera or post-essential thrombocythemia myelofibrosis.

Protocol

• Protocol: Kinase Assay ^[1]
• Cell-free kinase activity assays: Glutathione-S-transferase (GST)-tagged JAK kinase domains expressed in insect cells are purified before use in a peptide substrate phosphorylation assay. Assays are carried out in 384-well optiplates using an Alphascreen Protein Tyrosine Kinase P100 detection kit and a PerkinElmer Fusion Alpha instrument.
• Protocol: Cell Assay ^[1]
• Cell Lines: Ba/F3, Ba/F3-JAK2V617F and Ba/F3-MPLW515L cells
• Concentrations: 0 to 10 μM
• Incubation Time: 72 hours
• Methods: Ba/F3 cells expressing JAK2V617F (Ba/F3-JAK2V617F) and MPLW515L (Ba/F3-MPLW515L) mutants, as well as CHRF-288-11 (JAK2T875N) and CMK (JAK3A572V) cells are used. The TEL/JAK2 and TEL/JAK3 fusions are generated and introduced into Ba/F3 murine cells. The TEL/JAK2- or TEL/JAK3-transfected cells are cultured in Dulbecco’s modified Eagle’s medium (DMEM) containing 10% fetal calf serum (FCS). Ba/F3 wild-type cells are cultured in RPMI containing 10% FCS supplemented with 5 ng/mL murine IL-3. Proliferation is measured using the Alamar Blue assay after incubating for 72 hours at 37 °C with 5% CO₂.
• Protocol: Animal Study ^[3]
• Animal Models: Balb/c mice are transplanted with bone marrow transduced with a JAK2V617F retrovirus.
• Formulation: CYT387 is dissolved in NMP (120 mg/mL final; 1-methyl-2-pyrrolidinone, Chromasolv Plus). Subsequently, the CYT387/NMP mix is diluted with 0.14 M Captisol to a concentration of 6 mg/mL and further diluted with 0.1M Captisol to a final concentration of 4 mg/mL.
• Doses: ≤50 mg/kg
• Administration: Administered via p.o.

References

• References: [1] Pardanani A, et al. Leukemia, 2009, 23(8), 1441-1445.
• References: [2] Monaghan KA, et al. Leukemia, 2011, 25(12), 1891-1899.
• References: [3] Tyner JW, et al. Blood, 2010, 115(25), 5232-5240.

参考文献

• Pardanani A, et al. Leukemia, 2009, 23(8), 1441-1445.
• Monaghan KA, et al. Leukemia, 2011, 25(12), 1891-1899.
• Tyner JW, et al. Blood, 2010, 115(25), 5232-5240.