GSK1838705A

Molecular Weight: 532.57 GSK1838705A is a potent IGF-1R Inhibitor with IC50 of 2.0 nM, modestly potent to IR and ALK with IC50 of 1.6 nM and 0.5 nM, respectively, and little activity to other protein kinases.


Biological Activity


GSK1838705A potently and ATP-competitively inhibits IGF-1R and IR with appKi values of 0.7 nM and 1.1 nM, respectively.In cells, GSK1838705A
potently inhibits ligand-induced phosphorylation of IGF-1R and IR with
IC50 of 85 nM and 79 nM, respectively. GSK1838705A shows the significant
anti-proliferative effect in a panel of cell lines derived from solid
and hematologic tumors such as L-82, SUP-M2, SK-ES and MCF-7 cells with
EC50 of 24 nM, 28 nM, 141 nM and 203 nM, respectively.




GSK1838705A shows
an accumulation of MCF-7 and NCl-H929 cells predominantly in G1 (2N)
phase of the Cell Cycle. GSK1838705A also inhibits ALK with Ki of 0.35 nM and supresses the proliferation of nucleophosmin (NPM)-ALK
fusion cells with EC50 of 24-88 nM. GSK1838705A potently inhibits
NPM-ALK phosphorylation in Karpas-299 and SR-786 cells, while has modest
effect on STAT3 phosphorylation.






In NIH-3T3/LISN tumor-bearing mice, oral treatment of GSK1838705A (60
mg/kg) cause tumor growth inhibition by 77%, without significant weight
loss. In COLO 205 tumor-bearing mice, inhibition of tumor growth by
GSK1838705A (30 mg/kg) is 80%. Besides, the antitumor efficacy of
GSK1838705A is also observed in mice bearing HT29 xenograft or BxPC3
xenograft.




In mice, GSK1838705A (60 mg/kg) leads to a transient 2-fold
increase in blood glucose levels by inhibiting IR signaling. GSK1838705A
(60 mg/kg) inhibits the growth of established Karpas-299 xenografts
with 93% tumor growth inhibition, with no effect on weights of the rats.


Kinase Assays


Baculovirus-expressed glutathione S-transferase-tagged Proteins encoding
the intracellular domain of IGF-1R (Amino Acids 957-1367) and IR (amino
acids 979-1382) are used for determinations of IC50s by a homogeneous
time-resolved fluorescence assay. A filter binding assay is used for
appKi determinations using activated IGF-1R and IR kinases. Expanded
kinase-selectivity profiling of GSK1838705A is carried out by screening
the compound in the KinaseProfiler panel.


Method


Cells are seeded in 96-well dishes, incubated overnight at 37 °C, and
treated with DMSO or GSK1838705A for 72 hours. For the NIH-3T3/LISN
proliferation assays, cells are seeded on collagen-coated 96-well tissue
culture plates and allowed to adhere for 24 hours. The medium is
replaced with serum-free medium and the cells are treated with
GSK1838705A for 2 hour. Cells are incubated for 72 hours after addition
of IGF-I (30 ng/mL). Cell proliferation is quantified using the
CellTiter-Glo Luminescent Cell Viability Assay. IC50s are determined
from cytotoxicity curves using a four-parameter curve fit software
package (XLfit4

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Product Categories : Protein Tyrosine Kinase > ALK Inhibitor