CP-673451
Product Description
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Molecular Weight: 417.5 CP-673451 is a selective inhibitor of PDGFRα/β with IC50 of 10 nM/1 nM, exhibits >450-fold selectivity over other angiogenic receptors, has antiangiogenic and antitumor activity.
Biological Activity
CP 673451 is a selective inhibitor of PDGFRα/β with IC50 of 10 nM/1 nM,
exhibits >450-fold selectivity over Other angiogenic receptors. In
glioblastoma tumors, CP-673451 (33 mg/kg) provides >50% inhibition of
PDGFR-β receptor for 4 hours corresponding to an EC50 of 120 ng/mL in
plasma at Cmax. In a sponge Angiogenesis model, CP-673451
inhibits 70% of PDGF-BB-stimulated angiogenesis at a dose of 3 mg/kg
(q.d. ×5, p.o., corresponding to 5.5 ng/mL at Cmax). CP-673451 decreases cell proliferation rate through mechanisms
involving reduced phosphorylation of GSK-3α and GSK-3β. In both RD and
RUCH2 cultures, CP-673451 impairs rhabdosphere-forming capacity and cell
differentiation, causes increased senescence.
CP 673451 (once-daily p.o. ?0 days dosing routinely) inhibits tumor
growth (ED50 In RUCH2 xenograft-bearing mice, CP 673451 reduces
tumor growth and stromal cell infiltration.
Kinase inhibition assay
A glutathione S-transferase-tagged kinase domain construct of the
intracellular portion of the PDGFR-β (Amino Acids 693-1401, accession
no. J03278) is expressed in Sf-9 cells (baculovirus expression system).
Enzyme kinetics are determined by incubating the enzyme with increasing
concentrations of ATP in phosphorylation buffer [50 mmol/L HEPES (pH
7.3), 125 mmol/L NaCl, 24 mmol/L MgCl2 in Nunc Immuno
MaxiSorp 96-well plates previously coated with 100 μL of 100 μg/mL
poly-Glu-Tyr (4:1 ratio) diluted in PBS.
After 10 minutes, the plates
are washed (PBS, 0.1% Tween 20), incubated with
anti-phosphotyrosine-horseradish peroxidase antibody, and diluted in
PBS, 0.05% Tween 20, 3% BSA for 30 minutes at room temperature. The
plates are washed as above and incubated with
3,3',5,5'-tetramethylbenzidine. The reaction is stopped by adding an
equal volume of 0.09 NaH2SO4. The
phosphotyrosine-dependent signal is then quantitated on a plate reader
at 450 nm.
For routine enzyme assays, the enzyme is incubated with 10 μM
( final) ATP in the presence of compound diluted in DMSO (1.6% v/v DMSO
assay final) for 30 minutes at room temperature in plates, as above,
previously coated with 100 μL of 6.25 μg/mL poly-Glu-Tyr. The remainder
of the assay is carried out as above, and IC50 values are calculated as
percent inhibition of control.
Method
PAE cells stably expressing full-length PDGFR and VEGFR have been
generated. For cell-based selectivity assays, PAE cells are transfected
with fulllength human PDGFR-a, PDGFR-h, or VEGFR-2. Cells are seeded at
4×105 cells/mL in 50 μL growth medium (Ham's F-12 media
supplemented with 10% fetal bovine serum, 50,000 units each penicillin
and streptomycin, and 500 μg/mL gentamicin) per well in 96-well plates.
After 6 to 8 hours, the growth medium is replaced with 50 μL
serum-depleted medium (as above, but with 0.1% fetal bovine serum) and
cells are incubated overnight.
Immediately before compound addition, the
medium was replaced with 95 μL serum-depleted medium. Compounds are
diluted in 100% DMSO, added to the cells at a final DMSO concentration
of 0.25% v/v, and incubated at 37°C for 10 minutes. Cells are stimulated
with the appropriate ligand and incubated as above for an additional 8
minutes. The medium is removed and the cells washed once with PBS, then
lysed with 50 μL HNTG buffer [20 mmol/L HEPES (pH 7.5), 150 mmol/L NaCl,
2% Triton X-100, 10% glycerol, 5 μmol/L EDTA, 2 mmol/L NaVO4,
and 1 EDTA-free complete protease inhibitor tablet per 25 mL] for 5
minutes at room temperature.
Lysates are then diluted with 50 μL HG
buffer [20 mmol/L HEPES (pH 7.5), 10% glycerol]. The diluted cell
lysates are mixed thoroughly, 50 μL of supernatant are transferred to
the ELISA capture plate, and incubated at room temperature for 2 hours
with agitation. ELISA capture plates are prepared by coating 96-well
ReactiBind goat-antirabbit plates with 100 μL/well of 5 μg/mL rabbit
anti-human PDGFR-h, anti-PDGFR-a, or anti-VEGFR-2 antibody for 60 to 90
minutes.
At the end of the 2-hour incubation the plates are washed (PBS,
0.1% Tween 20) before incubation with anti-phosphotyrosine-horseradish
peroxidase antibody (diluted in PBS, 0.05% Tween 20) for 30 minutes at
room temperature. The plates are washed again, then incubated with
tetramethylbenzidine and evaluated as described above. IC50 values are
calculated as percent inhibition of control.
Contact us if you need more details on 343787-29-1. We are ready to answer your questions on packaging, logistics, certification or any other aspects about CP-673451 343787-29-1、CP-673451. If these products fail to match your need, please contact us and we would like to provide relevant information.
Molecular Weight: 417.5 CP-673451 is a selective inhibitor of PDGFRα/β with IC50 of 10 nM/1 nM, exhibits >450-fold selectivity over other angiogenic receptors, has antiangiogenic and antitumor activity.
Biological Activity
CP 673451 is a selective inhibitor of PDGFRα/β with IC50 of 10 nM/1 nM,
exhibits >450-fold selectivity over Other angiogenic receptors. In
glioblastoma tumors, CP-673451 (33 mg/kg) provides >50% inhibition of
PDGFR-β receptor for 4 hours corresponding to an EC50 of 120 ng/mL in
plasma at Cmax. In a sponge Angiogenesis model, CP-673451
inhibits 70% of PDGF-BB-stimulated angiogenesis at a dose of 3 mg/kg
(q.d. ×5, p.o., corresponding to 5.5 ng/mL at Cmax). CP-673451 decreases cell proliferation rate through mechanisms
involving reduced phosphorylation of GSK-3α and GSK-3β. In both RD and
RUCH2 cultures, CP-673451 impairs rhabdosphere-forming capacity and cell
differentiation, causes increased senescence.
CP 673451 (once-daily p.o. ?0 days dosing routinely) inhibits tumor
growth (ED50 In RUCH2 xenograft-bearing mice, CP 673451 reduces
tumor growth and stromal cell infiltration.
Kinase inhibition assay
A glutathione S-transferase-tagged kinase domain construct of the
intracellular portion of the PDGFR-β (Amino Acids 693-1401, accession
no. J03278) is expressed in Sf-9 cells (baculovirus expression system).
Enzyme kinetics are determined by incubating the enzyme with increasing
concentrations of ATP in phosphorylation buffer [50 mmol/L HEPES (pH
7.3), 125 mmol/L NaCl, 24 mmol/L MgCl2 in Nunc Immuno
MaxiSorp 96-well plates previously coated with 100 μL of 100 μg/mL
poly-Glu-Tyr (4:1 ratio) diluted in PBS.
After 10 minutes, the plates
are washed (PBS, 0.1% Tween 20), incubated with
anti-phosphotyrosine-horseradish peroxidase antibody, and diluted in
PBS, 0.05% Tween 20, 3% BSA for 30 minutes at room temperature. The
plates are washed as above and incubated with
3,3',5,5'-tetramethylbenzidine. The reaction is stopped by adding an
equal volume of 0.09 NaH2SO4. The
phosphotyrosine-dependent signal is then quantitated on a plate reader
at 450 nm.
For routine enzyme assays, the enzyme is incubated with 10 μM
( final) ATP in the presence of compound diluted in DMSO (1.6% v/v DMSO
assay final) for 30 minutes at room temperature in plates, as above,
previously coated with 100 μL of 6.25 μg/mL poly-Glu-Tyr. The remainder
of the assay is carried out as above, and IC50 values are calculated as
percent inhibition of control.
Method
PAE cells stably expressing full-length PDGFR and VEGFR have been
generated. For cell-based selectivity assays, PAE cells are transfected
with fulllength human PDGFR-a, PDGFR-h, or VEGFR-2. Cells are seeded at
4×105 cells/mL in 50 μL growth medium (Ham's F-12 media
supplemented with 10% fetal bovine serum, 50,000 units each penicillin
and streptomycin, and 500 μg/mL gentamicin) per well in 96-well plates.
After 6 to 8 hours, the growth medium is replaced with 50 μL
serum-depleted medium (as above, but with 0.1% fetal bovine serum) and
cells are incubated overnight.
Immediately before compound addition, the
medium was replaced with 95 μL serum-depleted medium. Compounds are
diluted in 100% DMSO, added to the cells at a final DMSO concentration
of 0.25% v/v, and incubated at 37°C for 10 minutes. Cells are stimulated
with the appropriate ligand and incubated as above for an additional 8
minutes. The medium is removed and the cells washed once with PBS, then
lysed with 50 μL HNTG buffer [20 mmol/L HEPES (pH 7.5), 150 mmol/L NaCl,
2% Triton X-100, 10% glycerol, 5 μmol/L EDTA, 2 mmol/L NaVO4,
and 1 EDTA-free complete protease inhibitor tablet per 25 mL] for 5
minutes at room temperature.
Lysates are then diluted with 50 μL HG
buffer [20 mmol/L HEPES (pH 7.5), 10% glycerol]. The diluted cell
lysates are mixed thoroughly, 50 μL of supernatant are transferred to
the ELISA capture plate, and incubated at room temperature for 2 hours
with agitation. ELISA capture plates are prepared by coating 96-well
ReactiBind goat-antirabbit plates with 100 μL/well of 5 μg/mL rabbit
anti-human PDGFR-h, anti-PDGFR-a, or anti-VEGFR-2 antibody for 60 to 90
minutes.
At the end of the 2-hour incubation the plates are washed (PBS,
0.1% Tween 20) before incubation with anti-phosphotyrosine-horseradish
peroxidase antibody (diluted in PBS, 0.05% Tween 20) for 30 minutes at
room temperature. The plates are washed again, then incubated with
tetramethylbenzidine and evaluated as described above. IC50 values are
calculated as percent inhibition of control.
Contact us if you need more details on 343787-29-1. We are ready to answer your questions on packaging, logistics, certification or any other aspects about CP-673451 343787-29-1、CP-673451. If these products fail to match your need, please contact us and we would like to provide relevant information.
Product Categories : Protein Tyrosine Kinase > PDGFR Inhibitor
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