CP-673451

Alias: CP-673451; CP673451; CP 673451; CP-673,451; CP 673,451
Cat No.:V0577 Purity: ≥98%
CP-673451 (CP673451) is a novel, potent, selective and ATP-competitive inhibitor of PDGFR(α/β) with potential antitumor activity.
CP-673451 Chemical Structure CAS No.: 343787-29-1
Product category: PDGFR
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

CP-673451 (CP673451) is a novel, potent, selective and ATP-competitive inhibitor of PDGFR(α/β) with potential antitumor activity. It exhibits >450-fold selectivity for PDGFR(α/β) over other angiogenic receptors and inhibits PDGFR(α/β) with IC50s of 10 nM/1 nM in cell-free assays. There are antiangiogenic and antitumor properties to CP-673451. and is being looked into as a possible cancer treatment. While high-dose CP-673451 (40 mg/kg) strongly inhibits tumor growth in mice without significantly reducing weight, CP-673451 exhibits excellent anti-proliferative activity in vitro and high in vivo antitumor efficacy (at 20 mg/kg) with a medium suppression of tumor growth.

Biological Activity I Assay Protocols (From Reference)
Targets
PDGFRα (IC50 = 10 nM); PDGFRβ (IC50 = 1 nM)
ln Vitro

CP 673451 demonstrates >450-fold selectivity over other angiogenic receptors and is a selective inhibitor of PDGFRα/β with an IC50 of 10 nM/1 nM. For four hours, CP-673451 (33 mg/kg) in glioblastoma tumors inhibits the PDGFR-β receptor by more than 50%, resulting in an EC50 of 120 ng/mL in plasma at Cmax. In an angiogenesis model involving sponges, CP-673451 at 3 mg/kg (q.d. ×5, p.o., or 5.5 ng/mL at Cmax) inhibits 70% of PDGF-BB-stimulated angiogenesis.[1] Through mechanisms involving reduced phosphorylation of GSK-3α and GSK-3β, CP-673451 reduces the rate of cell proliferation. CP-673451 inhibits rhabdosphere-forming ability and cell differentiation, leading to increased senescence in both RD and RUCH2 cultures.[2]

ln Vivo
CP 673451 (once-daily p.o.?0 days dosing regularly) inhibits tumor growth (ED50 < 33 mg/kg) in several human tumor xenografts grown s.c. in athymic mice, such as U87MG human glioblastoma multiforme, Colo205 and LS174T human colon carcinomas, and H460 human lung carcinoma.[1] CP 673451 inhibits tumor growth and stromal cell infiltration in RUCH2 xenograft-bearing mice.[2]
Enzyme Assay
Sf-9 cells (baculovirus expression system) express a glutathione S-transferase-tagged kinase domain construct of the intracellular portion of PDGFR-β (amino acids 693-1401, accession no. J03278). The 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] is used to incubate the enzyme at increasing concentrations of ATP to determine the enzyme's kinetics. The plates are incubated with anti-phosphotyrosine-horseradish peroxidase antibody for 10 minutes, followed by a 30-minute room-temperature diluting step in PBS, 0.05% Tween 20, and 3% BSA. After the previously mentioned washing, the plates are incubated with 3,3',5,5'-tetramethylbenzidine. By adding an equal volume of 0.09 NaH2SO4, the reaction is terminated. Next, the phosphotyrosine-dependent signal is measured at 450 nm using a plate reader. For standard enzyme tests, the enzyme is incubated for 30 minutes at room temperature with 10 μM (final) ATP in the presence of a compound diluted in DMSO (1.6% v/v DMSO assay final) in the previously mentioned plates coated with 100 μL of 6.25 μg/mL poly-Glu-Tyr. The assay is completed as previously described, and IC50 values are computed as a percentage of control's inhibition.
Cell Assay
It is possible to generate PAE cells that express full-length PDGFR and VEGFR consistently. Full-length human PDGFR-a, PDGFR-h, or VEGFR-2 are transfected into PAE cells in order to perform cell-based selectivity assays. 50 μL of growth medium (Ham's F-12 media supplemented with 10% fetal bovine serum, 50,000 units of penicillin and streptomycin, and 500 μg/mL gentamicin) is used per well in 96-well plates to seed cells at a density of 4×103 cells/mL. After 6 to 8 hours, the cells are incubated overnight in 50 μL of serum-depleted medium (as above, but with 0.1% fetal bovine serum) in place of the growth medium. 95 μL of serum-depleted medium was added to the medium just before the compound was added. The compounds are added to the cells at a final DMSO concentration of 0.25% v/v after being diluted in 100% DMSO, and they are then incubated for 10 minutes at 37°C. The proper ligand is used to stimulate the cells, and they are then incubated for a further eight minutes. The medium is taken out, and the cells are rinsed once with PBS before being lysed for five minutes at room temperature in 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). 50 μL of HG buffer (20 mmol/L HEPES (pH 7.5), 10% glycerol)] is then added to the lysates to dilute them. Once the diluted cell lysates are well combined, 50 μL of the supernatant is added to the ELISA capture plate and it is incubated for two hours at room temperature while being stirred. Coating 96-well ReactiBind goat-antirabbit plates with 100 μL/well of rabbit anti-human PDGFR-h, anti-PDGFR-a, or anti-VEGFR-2 antibody for 60 to 90 minutes is the process used to prepare ELISA capture plates. Following a 2-hour incubation period, the plates are cleaned in PBS with 0.1% Tween 20 and then incubated for 30 minutes at room temperature with a diluted anti-phosphotyrosine-horseradish peroxidase antibody (PBS with 0.05% Tween 20). The plates are once more cleaned, tetramethylbenzidine is added, and they are assessed as previously mentioned. Percentage inhibition of control is used to compute IC50 values.
Animal Protocol
The anticancer efficacy of CP-673451 is assessed in nude mice using a subcutaneous A549 xenograft model. In short, mice are given 2×106 cells/mouse of A549 cells injected into their axillary regions. Upon reaching 70 mm3, the mice are randomized into two groups: one for control and the other for CP-673451 (n = 6 per group) at low and high doses (20 mg/kg and 40 mg/kg, respectively) (vehicle 10% 1-methyl-2-pyrrolidinone and 90% polyethylene glycol 300). CP-673451 (20 or 40 mg/kg/day) or a vehicle is injected intraperitoneally into these animals. The implanted tumors are measured blindly once a day with a calliper during the course of treatment. Simultaneously, the animal body weights are measured. Tumor volume is computed. Following therapy, the tumors are removed and examined, and the mice are euthanized.
References

[1]. Cancer Res . 2005 Feb 1;65(3):957-66.

[2]. Cancer Res . 2013 Apr 1;73(7):2139-49.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C24H27N5O2
Molecular Weight
417.5
Exact Mass
417.22
Elemental Analysis
C, 69.04; H, 6.52; N, 16.77; O, 7.66
CAS #
343787-29-1
Appearance
Solid powder
SMILES
COCCOC1=CC2=C(C=C1)N(C=N2)C3=NC4=C(C=CC=C4N5CCC(CC5)N)C=C3
InChi Key
DEEOXSOLTLIWMG-UHFFFAOYSA-N
InChi Code
InChI=1S/C24H27N5O2/c1-30-13-14-31-19-6-7-21-20(15-19)26-16-29(21)23-8-5-17-3-2-4-22(24(17)27-23)28-11-9-18(25)10-12-28/h2-8,15-16,18H,9-14,25H2,1H3
Chemical Name
1-[2-[5-(2-methoxyethoxy)benzimidazol-1-yl]quinolin-8-yl]piperidin-4-amine
Synonyms
CP-673451; CP673451; CP 673451; CP-673,451; CP 673,451
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: ~28 mg/mL (~67.1 mM)
Water: <1 mg/mL
Ethanol: ~4 mg/mL (~9.6 mM)
Solubility (In Vivo)
30% PEG 400+5% propylene glycol+1% Tween 80+ddH2O: 30mg/mL
 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.3952 mL 11.9760 mL 23.9521 mL
5 mM 0.4790 mL 2.3952 mL 4.7904 mL
10 mM 0.2395 mL 1.1976 mL 2.3952 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

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Biological Data
  • CP-673451


  • CP-673451

    Impaired anchorage-independent rhabdosphere-forming capacity in cells devoid of PDGF activity. A, rhabdosphere formation in the presence of CP-673,451 or vehicle. B, rhabdosphere formation of cells pretreated 72 hours with CP-673,451 or vehicle in adherent cultures before seeding.

  • CP-673451

    PDGFR inhibition reduces tumor growth and stromal cell infiltration. A, growth of RUCH2 xenografts in response to CP-673,451 or vehicle (n≥6 mice/group). Cancer Res. 2013 Apr 1;73(7):2139-49.

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