AZD1480 935666-88-9

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Molecular Weight:

348.77 AZD1480 is a novel ATP-competitive JAK2 inhibitor with IC50 of 0.26 nM, selectivity against JAK3 and Tyk2, and to a smaller extent against JAK1. Phase 1.


Biological Activity


5μM AZD1480 induces G2/M arrest and cell death by inhibiting Aurora kinases. AZD1480 is a potent JAK2 inhibitor that can suppress growth, survival,
as well as FGFR3 and STAT3 signaling and downstream targets including
Cyclin D2 in human multiple myeloma cells. At low micromolar
concentrations, AZD1480 blocks cell proliferation and induces Apoptosis
of myeloma cell lines.


AZD1480 effectively blocks
constitutive and stimulus-induced JAK1, JAK2, and STAT-3 phosphorylation
in both human and murine glioma cells, and leads to a decrease in cell
proliferation and induction of apoptosis. AZD1480 is a
potent, competitive small-molecule inhibitor of JAK1/2 kinase, and that
it is capable of inhibiting STAT3 phosphorylation and tumor growth in a
STAT3-dependent manner. AZD1480 inhibits tumor Angiogenesis and
metastasis in part by affecting the tumor microenvironment.


AZD1480 inhibits the STAT3 phosphorylation in an xenograft model of human solid tumors and multiple myeloma. In vivo, AZD1480 inhibits the growth of subcutaneous tumors and
increases survival of mice bearing intracranial glioblastoma (GBM)
tumors by inhibiting STAT-3 activity, indicating that pharmacologic
inhibition of the JAK/STAT-3 pathway by AZD1480 should be considered for
study in the treatment of patients with GBM tumors.


AZD1480
blocks lung infiltration of myeloid cells and formation of pulmonary
metastases in both mouse syngeneic experimental and spontaneous
metastatic models. Furthermore, AZD1480 reduces angiogenesis and
metastasis in a human xenograft tumor model. The Jak2 inhibitor, AZD1480, suppresses the growth of human solid tumor xenografts harboring persistent Stat3 activity.






kinase assays


Inhibition studies of AZD1480 are performed using recombinant Jak1,
Jak2, or Jak3 under buffer conditions of 50 mM HEPES pH 7.3, 1 mM DTT,
0.01% Tween-20, 50 mM/ml BSA, and 10 mM MgCl2. Jak3 enzyme is
expressed as N-terminal GST fusion in insect cells and purified by
glutathione-affinity and size-exclusion chromatographies. Enzymes are
assayed in the presence of AZD1480 (10 point dose response, in
triplicate, from 8.3 μM to 0.3 nM in half-log dilution steps) using 1.5
μM peptide substrate (Jak1: FITC-C6-KKHTDDGYMPMSPGVA-NH2, Jak2 and Jak3:
FAM-SRCtide) and screened under their respective ATP Km (Jak1: 55 μM,
Jak2: 15 μM, Jak3: 3 μM) and approximated physiological ATP
concentration of 5 mM. Phosphorylated and unphosphorylated peptides are
separated and quantified by a Caliper LC3000 system for calculating
percent inhibition.

Method

Renca or 786-O cells are suspended in DMEM medium with 5% FBS , and seeded in 96-well plates (5×103 per well) to allow adhesion and then treated with DMSO or AZD1480 for
48 hours. Cell viability is determined by MTS assay. Absorbance at 490
nm is measured with Mikrotek Laborsysteme.


Mouse endothelial cells and
splenic CD11b+/c- myeloid cells are enriched from
tumor-bearing mice,and cultured in 5% FBS RPMI-1640 medium. HUVECs are
cultured on collagen 1–coated plates in complete medium. All cells are
treated with DMSO and AZD1480 at various doses for 24 hours. Cell
viability is determined by counting cell number manually. All the
experiments are repeated 3 times.

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