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1056634-68-4

1056634-68-4 structure
1056634-68-4 structure
  • Name: CYT387
  • Chemical Name: N-(Cyanomethyl)-4-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)benzamide
  • CAS Number: 1056634-68-4
  • Molecular Formula: C23H22N6O2
  • Molecular Weight: 414.460
  • Catalog: Biochemical Inhibitor Protein tyrosine kinase
  • Create Date: 2018-12-23 10:22:42
  • Modify Date: 2024-01-03 19:04:53
  • Momelotinib (CYT387) is an ATP-competitive inhibitor of JAK1/JAK2 with IC50a of 11 nM and 18 nM,respectively. CYT387 shows much less activity against JAK3.
Name N-(Cyanomethyl)-4-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)benzamide
Synonyms N-(Cyanomethyl)-4-(2-((4-morpholinophenyl)-amino)pyrimidin-4-yl)benzamide
N-(Cyanomethyl)-4-(2-{[4-(4-morpholinyl)phenyl]amino}-4-pyrimidinyl)benzamide
Benzamide, N-(cyanomethyl)-4-[2-[[4-(4-morpholinyl)phenyl]amino]-4-pyrimidinyl]-
Momelotinib
CYT387
CYT-387
Description Momelotinib (CYT387) is an ATP-competitive inhibitor of JAK1/JAK2 with IC50a of 11 nM and 18 nM,respectively. CYT387 shows much less activity against JAK3.
Related Catalog
Target

JAK1:11 nM (IC50)

JAK2:18 nM (IC50)

JAK3:155 nM (IC50)

In Vitro Momelotinib (CYT387) inhibits the proliferation of parental Ba/F3 cells (Ba/F3-wt) stimulated by IL-3 with IC50 of 1400 nM. Furthermore, Momelotinib (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, Momelotinib (CYT387) has been shown to inhibit erythroid colony growth in vitro from JAK2V617F-positive PV patients with similar potency with IC50 of 2 μM-4 μM[1]. Momelotinib (CYT387) inhibits PI3K/AKT and Ras/MAPK signaling induced by IL-6 and IGF-1. Moreover, Momelotinib (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, Momelotinib (CYT387) normalizes white cell counts, hematocrit, spleen size, and restores physiologic levels of inflammatory cytokines[3].
Kinase Assay 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 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 Admin On day 32 after bone marrow transplantation (when all mice exhibit severe leukocytosis and erythrocytosis), mice are assigned to 3 groups such that each group had equivalent average body weight and blood counts. Momelotinib (CYT387) is dissolved in NMP (120 mg/mL final; 1-methyl-2-pyrrolidinone). 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. All 3 groups of mice (n=12 per group) are administered Momelotinib (CYT387) by oral gavage twice daily at 10- to 12-hour intervals from day 34 after bone marrow transplantation to day 82 (end of experiment). Mice receive NMP/Captisol without Momelotinib (CYT387) (0 mg/kg group), 25 mg/kg Momelotinib (CYT387), or 50 mg/kg Momelotinib (CYT387). At day 82 after bone marrow transplantation, all mice are euthanized for analysis except for 2 mice each from the 50 mg/kg and 25 mg/kg groups, which are taken off Momelotinib (CYT387) treatment and followed for 45 additional days. For assessment of the effects of CYT387 on normal blood counts, naive Balb/c mice are administered vehicle control, 50 mg/kg, or 100 mg/kg Momelotinib (CYT387) in an identical fashion as described for the bone marrow transplant experimental mouse cohort. Peripheral blood is drawn at day 14, 28, 42, and 56 and levels of red cells, white cells, reticulocytes, granulocytes, lymphocytes, and monocytes are analyzed[3].
References

[1]. Pardanani A, et al. CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. Leukemia, 2009, 23(8), 1441-1445.

[2]. Monaghan KA, et al. The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells. Leukemia, 2011, 25(12), 1891-1899.

[3]. Tyner JW, et al. CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood, 2010, 115(25), 5232-5240.

[4]. Kitajima S, et al.Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS.Cancer Cell. 2018 Sep 10;34(3):439-452.e6. doi: 10.1016/j.ccell.2018.08.009.
Density 1.3±0.1 g/cm3
Molecular Formula C23H22N6O2
Molecular Weight 414.460
Exact Mass 414.180420
PSA 103.17000
LogP 1.22
Index of Refraction 1.646
Hazard Codes Xi
HS Code 2934999090
945749-71-3 structure

945749-71-3

6011-14-9 structure

6011-14-9

~90%

1056634-68-4 structure

1056634-68-4

Literature: CYTOPIA RESEARCH PTY LTD Patent: WO2008/109943 A1, 2008 ; Location in patent: Page/Page column 58 ; WO 2008/109943 A1
Precursor  2

DownStream  0

HS Code 2934999090
Summary 2934999090. other heterocyclic compounds. VAT:17.0%. Tax rebate rate:13.0%. . MFN tariff:6.5%. General tariff:20.0%

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