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Cyt387

产品号 S2219 公司名称 Selleck Chemicals
CAS号 1056634-68-4 公司网站 http://www.selleckchem.com
分子式 C23H22N6O2 电 话 (877) 796-6397
分子量 414.45978 传 真 (832) 582-8590
纯 度 电子邮件 sales@selleckchem.com
保 存 -20°C Chembase数据库ID: 72907

产品价格信息

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产品别名

标题
Cyt387
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

产品登记号

CAS号 1056634-68-4

产品性质

作用靶点 JAK
成盐信息 Free Base
保存条件 -20°C

产品详细信息

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