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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T98GMUfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?NYCwWWY1UUN3ME20O{42PDdizszNMnfiV2FPT0WU
OVCAR-8NEPjc4FIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=MYXJR|UxRTR5Lk[4N{DPxE1?NV;0fmdqW0GQR1XS
LB2241-RCCM{\odmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7M13OSmlEPTB;NEeuO|I4KM7:TR?=MmTwV2FPT0WU
NCI-H358NHW4eI1Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?=MWnJR|UxRTR6LkGxOVIh|ryPMmXpV2FPT0WU
PANC-08-13NXzx[nNOT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=NH;4NlNKSzVyPUS4MlE5PTNizszNNEHIdHhUSU6JRWK=
KP-N-YNMWHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?MonwTWM2OD12OD6yNVAzKM7:TR?=MVjTRW5ITVJ?
NCI-H1755MlzyS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?MXnJR|UxRTR6LkK3NlYh|ryPNF3rW3hUSU6JRWK=
NCI-N87NInhXpNIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=NUj2bpM3UUN3ME20PE4zQTlzIN88US=>M4fHb3NCVkeHUh?=

... 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)
* <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

Customer Product Validation(6)


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Rating
Source Science 2011 331(6019), 912-6. PD173074 purchased from Selleck
Method Immunohistochemistry
Cell Lines uterine horn
Concentrations
Incubation Time
Results The epithelia of vehicle-treated horn showed prominent expression of p-FRS2 and p-ERK1/2 (Fig. A, a and c). However, the levels of both p-FRS2 and p-ERK1/2 were reduced in the epithelia of PD173074-treated horn on day 4 of pregnancy (Fig. A, b and d). We also observed a marked decline in the proliferative activity of Hand2-null uterine epithelia, as indicated by decreased Ki-67 staining (Fig. A, e and f). Administration of either PD173074 (Fig. C, a to d) or PD184352 (Fig. C, e to h) to Hand2-null uterine horns blocked the phosphorylation of epithelial ER a at Ser118 and the expression of Muc-1.

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Rating
Source Cancer Discov 2013 3(6), 636-47. PD173074 purchased from Selleck
Method Western blot
Cell Lines SW780 cells
Concentrations 10, 40 mg/kg
Incubation Time
Results Similar results for FGFR fusion-positive lines were obtained in vivo. SW780 xenografts exhibited decreased tumor growth with increasing doses of PD173074.

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Rating
Source Hepatology 2014 59(4) ,1427-34. PD173074 purchased from Selleck
Method Western blot
Cell Lines NIH3T3 cells
Concentrations 0.2, 1 uM
Incubation Time 2 h
Results It examined the sensitivity of FGFR2 fusion-driven tumor cells to two specific FGFR inhibitors, BGJ398 and PD173074, which selectively inhibit FGFR tyrosine kinase activity. PD173074 significantly inhibited the phosphorylation of MAPK and reduced in vitro anchorage-independent colony formation to the level observed in KD mutant expressing cells.

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Rating
Source PLoS Genet 2012 8(2), e1002500. PD173074 purchased from Selleck
Method Immunohistochemistry
Cell Lines Msx1d/dMsx2d/d mice
Concentrations 50 uM
Incubation Time 24 h
Results PD173074, a FGFR-specific inhibitor, or vehicle into uterine horns of Msx1d/dMsx2d/d mice in the pre-implantation phase. As shown in Figure, the epithelia of vehicle-treated uterine horns of these mice showed strong expression of phospho-FRS2 on day 4 of pregnancy (panel a). Treatment with the PD173074 led to a marked reduction in the level of phospho-FRS2 in the uterine epithelium (panel b). Concomitant with this down regulation of FGFR signaling, it observed a decline in the proliferative activity of Msx1Msx2-null uterine epithelia as well as down-regulation of MUC-1 expression (panels c–f).

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Rating
Source Biochem Bioph Res Co 2012 11(9), 745-57. PD173074 purchased from Selleck
Method Western Blot
Cell Lines 293MSR-GT
Concentrations 15 uM
Incubation Time 48 h
Results we noticed that inhibition of activity of several receptor Tyr kinases (RTKs) (or of their downstream signaling), especially the FGFRs, with small molecules (e.g. SU5402, SU6668, PD173074, EKI-785/CL-387,785, Ki8751) led to a robust rescue of DF508-CFTR (Fig. 1).

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Rating
Source J Cell Sci 2014 10.1242/jcs.159608. PD173074 purchased from Selleck
Method Real time microscopy
Cell Lines GFP-MPR cells
Concentrations 10 uM
Incubation Time 1 h
Results Incubation with the FGFR inhibitor PD173074 for 1h caused the fragmentation of the perinuclear GFP-MPR compartment (91?4% of the cells, mean ?s.d., n = 3 experiments) , thus mimicking FGFR1 knockdown.

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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