Momelotinib (CYT387) 1056634-68-4

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Molecular Weight:

414.46 Momelotinib (CYT387) is an ATP-Competitive Inhibitor of JAK1/JAK2 with IC50 of 11 nM/18 nM, ~10-fold selectivity versus JAK3. Phase 3.


Biological Activity


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.


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.


In a murine MPN model, CYT387 normalizes white cell counts, hematocrit,
spleen size, and restores physiologic levels of inflammatory cytokines.


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.

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

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Product Categories : Epigenetics > JAK Inhibitor