CYT387

CYT387 is an ATP-competitive inhibitor of JAK1/JAK2 with IC50 of 11 nM/18 nM, ~10-fold selectivity versus JAK3. Phase 3.

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CYT387 Chemical Structure

CYT387 Chemical Structure
Molecular Weight: 414.46

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Product Description

Biological Activity

Description CYT387 is an ATP-competitive inhibitor of JAK1/JAK2 with IC50 of 11 nM/18 nM, ~10-fold selectivity versus JAK3. Phase 3.
Targets JAK1 JAK2 JAK3
IC50 11 nM [1] 18 nM [1] 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]
Features

Protocol(Only for Reference)

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
Method 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.
Dosages ≤50 mg/kg
Administration Administered via p.o.
Solubility 30% PEG400/0.5% Tween80/5% propylene glycol, , 30 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
1

References

[1] Pardanani A, et al. Leukemia, 2009, 23(8), 1441-1445.

[2] Monaghan KA, et al. Leukemia, 2011, 25(12), 1891-1899.

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Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01969838 Recruiting Primary Myelofibrosis|Post-Polycythemia Vera Myelofibrosis|Post-Essential Thrombocythemia Myelofibrosis Gilead Sciences 2013-10 Phase 3
NCT01998828 Recruiting Polycythemia Vera|Essential Thrombocythemia Gilead Sciences 2014-02 Phase 2
NCT02124746 Enrolling by invitation Primary Myelofibrosis|Post-Polycythemia Vera Myelofibrosis|Post-Essential Thrombocythemia Myelofibrosis|Polycythemia Vera|Essential Thrombocythemia Gilead Sciences 2014-04 Phase 2
NCT02101021 Not yet recruiting Metastatic Pancreatic Ductal Adenocarcinoma Gilead Sciences 2014-06 Phase 2
NCT02101268 Not yet recruiting Primary Myelofibrosis (PMF),|Post-polycythemia Vera (Post-PV)|Post-essential Thrombocythemia Myelofibrosis (Post-ET MF) Gilead Sciences 2014-06 Phase 3

Chemical Information

Download CYT387 SDF
Molecular Weight (MW) 414.46
Formula

C23H22N6O2

CAS No. 1056634-68-4
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms LM-1149
Solubility (25°C) * In vitro DMSO 83 mg/mL (200 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol, 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide

Research Area

Customer Reviews (1)


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Rating
Source Blood, 2012, 120(19):4093-103. CYT387 purchased from Selleck
Method Flow cytometric analysis
Cell Lines WT pan T cells
Concentrations 1 uM
Incubation Time
Results CYT387 dramatically reduced the expression of CXCR3 in activated WT T cells.

Product Citations (2)

Tech Support & FAQs

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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