NVP-ADW742 475488-23-4

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Molecular Weight:

453.58 NVP-ADW742 is an IGF-1R Inhibitor with IC50 of 0.17 μM, >16-fold more potent against IGF-1R than InsR; little activity to HER2, PDGFR, VEGFR-2, Bcr-Abl and c-Kit.


Biological Activity


NVP-ADW742 exhibits a 6-fold greater selectivity for IGF-1R versus InsR
with IC50 of 2.8 μM; minimal inhibitory activity against c-Kit, HER1,
PDGFR, VEGFR2, or Bcr-Abl p210 with IC50 greater than 5 μM. NVP-ADW742
significantly inhibits the serum-stimulated cell proliferation in a
variety of tumor cell lines in dose-dependent manner, with IC50 values
of 0.1-0.5 μM for the multiple myeloma (MM) cell lines, and the
antitumor effects on MM cells can not be overcome by the co-culture with
BMSCs. NVP-ADW742 also abrogates the responsiveness of tumor cells to
IL-6 in the presence of serum.


In addition, NVP-ADW742 is active against
MM cell lines with resistance to conventional (cytotoxic chemotherapy,
dexamethasone) or investigational (thalidomide, CC-5013, TRAIL/Apo2L,
PS-341) anticancer agents, as well as primary tumor cells from MM
patients with multi-drug-resistant disease. NVP-ADW742 decreases the
production of VEGF by tumor cells and bone marrow stromal cells, and
suppresses the IGF-1-induced secretion of VEGF by various tumor types
such as thyroid cancer cells or MM cells.


IGF-1R inhibition by
NVP-ADW742 (0.75 μM) sensitizes MM cells or prostate cancer cells to
other anticancer agents such as doxorubicin, melphalan, dexamethasone,
TRAIL/Apo2L, or PS-341.


Administration of NVP-ADW742 at 10 mg/kg twice daily significantly
inhibits tumor growth, prolongs survival, and enhances the antitumor
effect of cytotoxic chemotherapy melphalan in the mice model of diffuse
MM.






Cellular kinase activity assay


The IC50 value for the effect of NVP-ADW742 on the autophosphorylation
of IGF-1R is determined at the cellular level in the presence of
increasing concentrations of NVP-ADW742, using 96-well [Capture ELISAs"
assays. Briefly, NWT-21 cells are seeded into 96-well tissue culture
plates in complete growth medium and grown to 70-80% confluency, and are
then starved for 24 hours in 0.5% FCS medium. Subsequently, cells are
incubated for 90 minutes in the presence of NVP-ADW742 followed by the
stimulation with of IGF-I (10 ng/mL) for 10 minutes at 37 °C.


Subsequently, the cells are washed twice with ice-cold PBS and lysed at 4
°C with 50 μL/well RIPA-buffer (50 mM Tris-HCl, pH 7.2, 120 mM NaCl, 1
mM EDTA, 6 mM EGTA, 1% NP-40, 20 mM NaF, 1 mM benzamidine, 15 mM sodium
pyrophosphate, 1 mM PMSF and 0.5 mM Na3VO4). The
lysates from each experiment are then transferred to black ELISA plates
precoated with capture antibodies specific for IGF-1R.


After capture by
the antibodies, lysates are mixed with 40 μL of an alkaline phosphatase
(AP) labelled anti-phosphotyrosine Ab (PY20(AP) diluted to 0.2 μg/mL in
RIPA buffer, and incubated overnight at 4 °C. After washing (PBST) and
incubation for 45 minutes at RT with the luminescent AP-substrate
CDPStar RTU with Emerald II (90 μL/well), luminescence is measured using
a Packard Top Count Scintillation Counter.

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Product Categories : Protein Tyrosine Kinase > IGF-1R Inhibitor