PD173074 Licensed by Pfizer

Catalog No.S1264

PD173074 is a potent FGFR1 inhibitor with IC50 of ~25 nM and also inhibits VEGFR2 with IC50 of 100-200 nM in cell-free assays, ~1000-fold selective for FGFR1 than PDGFR and c-Src.

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PD173074 Chemical Structure

PD173074 Chemical Structure
Molecular Weight: 523.67

Validation & Quality Control

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Quality Control & MSDS

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Product Information

  • Compare FGFR Inhibitors
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  • Research Area
  • Inhibition Profile
  • PD173074 Mechanism
  • Combination Therapy
    Combination Therapy

Product Description

Biological Activity

Description PD173074 is a potent FGFR1 inhibitor with IC50 of ~25 nM and also inhibits VEGFR2 with IC50 of 100-200 nM in cell-free assays, ~1000-fold selective for FGFR1 than PDGFR and c-Src.
Targets FGFR1 [1]
(Cell-free assay)
VEGFR2 [1]
(Cell-free assay)
c-Src [1]
(Cell-free assay)
EGFR [1]
(Cell-free assay)

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IC50 ~25 nM 100 nM-200 nM 19.8 μM >50 μM
In vitro PD173074 is an ATP-competitive inhibitor of FGFR1 with Ki of ~40 nM. PD173074 is also an effective inhibitor of VEGFR2. Compared to FGFR1, PD173074 weakly inhibits the activities of Src, InsR, EGFR, PDGFR, MEK, and PKC with 1000-fold or greater IC50 values. PD173074 inhibits autophosphorylation of FGFR1 and VEGFR2 in a dose-dependent manner with IC50 of 1-5 nM and 100-200 nM, respectively. [1] PD173074 inhibits FGF-2 promotion of granule neuron survival in a dose-dependent manner with IC50 of 12 nM, exhibiting 1,000-fold greater potency than that of SU 5402. [2] PD173074 specifically inhibits FGF-2-mediated effects on proliferation, differentiation, and MAPK activation in oligodendrocyte (OL) lineage cells. [3] PD173074 is active against the WT receptor and FGFR3 mutations in multiple myeloma (MM) cell lines. PD173074 also potently inhibits autophosphorylation of FGFR3 in a dose-dependent manner with IC50 of ~5 nM. PD173074 treatment potently reduces viability of FGFR3-expressing KMS11 and KMS18 cells with IC50 of <20 nM. Inhibition of aFGF-stimulated MM cell growth by PD173074 is highly correlated with the expression of FGFR3. PD173074 treatment completely abolishes NIH 3T3 transformation mediated by Y373C FGFR3 but not by Ras V12, demonstrating that PD173074 specifically targets FGFR3-mediated cell transformation and lacks nonspecific cytotoxic effect. PD173074 also induces functional maturation of KMS11 and KMS18 cells. [4]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
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NUGC-3Mn;yS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?NYDJXXZOUUN3ME20Ok42PzB7IN88US=>M13OUHNCVkeHUh?=
T98GNVq1UYU5T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=NXXjOY1[UUN3ME20O{42PDdizszNM1TWOXNCVkeHUh?=
OVCAR-8M1;FT2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7M2H0RWlEPTB;NEeuOlg{KM7:TR?=NWLITolMW0GQR1XS
LB2241-RCCNH[wVJdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=NHzae5JKSzVyPUS3MlczPyEQvF2=M2rV[XNCVkeHUh?=
NCI-H358MXXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?NUHEe2g2UUN3ME20PE4yOTV{IN88US=>NELxdXRUSU6JRWK=
PANC-08-13NGHWVmtIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=M3LVdmlEPTB;NEiuNVg2OyEQvF2=MXLTRW5ITVJ?
KP-N-YNM1jyc2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7NXHnUYtQUUN3ME20PE4zOTB{IN88US=>NHTKellUSU6JRWK=
NCI-H1755NF61WmtIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=NWjOfnE3UUN3ME20PE4zPzJ4IN88US=>MXPTRW5ITVJ?
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... Click to View More Cell Line Experimental Data

In vivo Administration of PD173074 at 1 mg/kg/day or 2 mg/ka/day in mice can effectively block angiogenesis induced by either FGF or VEGF in a dose-dependent manner with no apparent toxicity. [1] PD173074 inhibits in vivo growth of mutant FGFR3-transfected NIH 3T3 cells in nude mice. Inhibition of FGFR3 by PD173074 delays tumor growth and increases survival of mice in a KMS11 xenograft myeloma model. [4] In the H-510 xenograft, oral aministration of PD173074 blocks tumor growth similar to that seen with single-agent cisplatin administration, increasing median survival compared with control sham-treated animals. In H-69 xenografts, PD173074 induces complete responses lasting >6 months in 50% of mice. These effects are correlated with increased apoptosis in excised tumors, but not a consequence of disrupted tumor vasculature. [5]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

In vitro kinase inhibition assays Assays using the full-length FGFR-1 kinase are performed in a total volume of 100 μL containing 25 mM HEPES buffer (pH 7.4), 150 mM NaCl, 10 mM MnCl2, 0.2 mM sodium orthovanadate, 750 μg/mL concentration of a random copolymer of glutamic acid and tyrosine (4:1), various concentrations of PD173074 and 60 to 75 ng of enzyme. The reaction is initiated by the addition of [γ-32P]ATP (5 μM ATP containing 0.4 μCi of [γ-32P]ATP per incubation), and samples are incubated at 25°C for 10 minutes. The reaction is terminated by the addition of 30% trichloroacetic acid and the precipitation of material onto glass-fiber filter mats. Filters are washed three times with 15% trichloroacetic acid, and the incorporation of [32P] into the glutamate tyrosine polymer substrate is determined by counting the radioactivity retained on the filters in a Wallac 1250 betaplate reader. Nonspecific activity is defined as radioactivity retained on the filters following incubation of samples without enzyme. Specific activity is determined as total activity (enzyme plus buffer) minus nonspecific activity. The concentration of PD173074 that inhibits FGFR-1 enzymatic activity by 50% (IC50) is determined graphically.

Cell Assay: [4]

Cell lines KMS11 and KMS18
Concentrations Dissolved in DMSO, final concentrations ~100 nM
Incubation Time 48 hours
Method Cells are incubated with increasing concentrations of PD173074 in the presence of aFGF/heparin for 48 hours. The percentage of viable cells is determined by MTT.

Animal Study: [1]

Animal Models Swiss Webster mice with induced corneal angiogenesis
Formulation Prepared in sterile fashion
Dosages ~2 mg/kg/day
Administration Administered intraperitoneally

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Mohammadi M, et al. EMBO J, 1998, 17(20), 5896-5904.

[2] Skaper SD, et al. J Neurochem, 2000, 75(4), 1520-1527.

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Chemical Information

Download PD173074 SDF
Molecular Weight (MW) 523.67
Formula

C28H41N7O3

CAS No. 219580-11-7
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 100 mg/mL (190.95 mM)
Ethanol 100 mg/mL (190.95 mM)
Water <1 mg/mL (<1 mM)
In vivo 5% DMSO+corn oil 15mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 1-tert-butyl-3-(2-(4-(diethylamino)butylamino)-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl)urea

Frequently Asked Questions

  • Question 1
    What is the half-life of PD173074(S1264) in vivo?

    Answer: According to literature research, PD173074 is given twice daily because it has a short half-life in vivo, please refer to the following link for detailed pharmacokinetic information (Supplementary Figure 8B): http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990281/#!po=50.0000.

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Tel: +1-832-582-8158 Ext:3

If you have any other enquiries, please leave a message.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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