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PD173074 Licensed by Pfizer

PD173074 is a potent FGFR1 inhibitor with IC50 of ~25 nM and also inhibits VEGFR2 with IC50 of 100-200 nM.

Catalog No.S1264

2 Reviews 5 Product Citations

: Tel: +1-832-582-8158[email protected]

PD173074 Chemical Structure
Molecular Weight: 523.67

Validation & Quality Control

Product Citations(5)

Science, 2011, 331(6019), 912-916

PLoS Genet, 2012, 8(2):e1002500

Mol Cell Proteomics, 2012, 11(9):745-57

PLoS One, 2013, 8(2), e56735

Clin Exp Metastasis, 2012, ahead of print

Customer Reviews(2) in vivo invitation

Quality Control & MSDS

Related Compound Libraries

PD173074 is available in the following compound libraries:

Cambridge Cancer Compound Library(96-well) Chemical Library (96-well) Inhibitor Library (96-well) Kinase Inhibitor Library (96-well) Pfizer Licensed Library Tyrosine Kinase Inhibitor Library (96-Well)

Product Information

Compare FGFR Inhibitors

Research Area
Research Area
PD173074 Mechanism
PD173074 Mechanism
FGFR1 consists of three extracellular immunoglobulin-like domains and an intracellular tyrosine kinase domain linked by a single hydrophobic membrane-spanning segment. The extracellular part is involved in the interaction with FGF. ^[1] The tyrosine kinase domain consists of an N-terminal lobe and a C-terminal lobe. The ATP binding site involves the residues in both N- and C-terminal lobe, while substrate peptide binding and catalysis are performed by residues in the C-terminal lobe. FGFR1 contains tyrosine autophosphorylation sites, including Tyr-463(juxtamembrane region), Tyr-583 and Tyr-585(kinase insert), Tyr-730 (core of the C-terminal lobe ), Tyr-653 and Tyr-654(activation loop). ^[2]
The crystal structure indicates that PD173074 binds in the ATP-binding pocket of FGFR1 kinase domain. Specifically, as the ATP adenine, the pyrido[2,3-d]pyrimidine ring system of PD173074 occupies the same pocket created by hydrophobic residues Leu484, Ala512, Tyr563, Ala564 and Leu630. PD 173074 makes two hydrogen bonds with main-chain atoms of hinge region, one from N-3 of the pyrimidine ring to the amide nitrogen of Ala564, and the other from the nitrogen of the butylamino group to the carbonyl oxygen of Ala564. In addition, a third hydrogen bond is made from one of the dimethoxy groups of PD173074 to the amide nitrogen of Asp641 in the activation. The urea group at the 7-position makes an internal hydrogen bond to N-8 of the pyrido[2,3-d]pyrimidine and is also hydrogen-bonded to a water molecule, which is in turn hydrogen-bonded to the side chains of Lys514 and Asp641. Besides, the dimethoxy phenyl group also makes van de Waals interactions with the side chains of Lys514, Glu531, Met535, Ile545, Val559, Val561, Ala640 and Phe642. The binding mode contributes to the potency and selectivity of PD173074. ^[3]
References
[1] Itoh N, et al. Biochem Biophys Res Commun. 1990, 169(2), 680-685.
[2] Mohammadi M, et al. Cell. 1996, 86(4), 577-587.
[3] Mohammadi M, et al. EMBO J. 1998, 17(20), 5896-5904.

Cat.No.	Product Name	Solubility (25°C)
S1490	Ponatinib (AP24534)	<1 mg/mL	30 mg/mL	<1 mg/mL
S2183	BGJ398 (NVP-BGJ398)	<1 mg/mL	32(heat) mg/mL	<1 mg/mL
S2801	AZD4547	<1 mg/mL	92 mg/mL	12 mg/mL
S1010	BIBF1120 (Vargatef)	<1 mg/mL	6 mg/mL	3 mg/mL
S1264	PD173074	<1 mg/mL	105 mg/mL	105 mg/mL
S1107	Danusertib (PHA-739358)	<1 mg/mL	95 mg/mL	<1 mg/mL
S1018	Dovitinib (TKI-258)	<1 mg/mL	30 mg/mL	<1 mg/mL
S1470	TSU-68 (SU6668)	<1 mg/mL	62 mg/mL	<1 mg/mL
S1084	Brivanib (BMS-540215)	<1 mg/mL	74 mg/mL	3 mg/mL
S2774	MK-2461	<1 mg/mL	99 mg/mL	<1 mg/mL
S2769	Dovitinib Dilactic acid (TKI258 Dilactic acid)	70 mg/mL	90 mg/mL	<1 mg/mL
S1138	Brivanib alaninate (BMS-582664)	<1 mg/mL	88 mg/mL	88 mg/mL
S8024	Tyrphostin AG 1296 (AG 1296)	<1 mg/mL	6 mg/mL	<1 mg/mL

Combination Therapy

Dr. Antonino Maria Sparta demonstrates a breakthrough in leukemia research by utilizing two inhibitors produced by Selleck Chemicals.

Product Description

Biological Activity Protocol Chemical Information Customer Reviews Product Citations Tech Support & FAQs

Biological Activity

Description	PD173074 is a potent FGFR1 inhibitor with IC50 of ~25 nM and also inhibits VEGFR2 with IC50 of 100-200 nM.
Targets	FGFR1	VEGFR2
IC50	~25 nM	100-200 nM ^[1]
In vitro	PD173074 is an ATP-competitive inhibitor of FGFR1 with K_i of ~40 nM. PD173074 is also an effective inhibitor of VEGFR2. Compared to FGFR1, PD173074 weakly inhibits the activities of Src, InsR, EGFR, PDGF, 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]
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]
Clinical Trials
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.

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

References

Chemical Information

Download PD173074 SDF

Molecular Weight (MW)	523.67
Formula	C₂₈H₄₁N₇O₃
CAS No.	219580-11-7
Synonyms	N/A

Solubility (25°C) DMSO 105 mg/mL Water <1 mg/mL Ethanol 105 mg/mL
Storage	2 years -20°CPowder
	2 weeks4°Cin DMSO
	6 months-80°Cin DMSO

Chemical Name	1-tert-butyl-3-(2-(4-(diethylamino)butylamino)-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl)urea

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Research Area

Customer Reviews (2)

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Rating

Source

SCIENCE, 2011, 331, 912-916. 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

Molecular & Cellular Proteomics , 2012. 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).

Product Citations (5)

The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2. [Li Q, et al. Science 2011;331(6019), 912-916]
PubMed: 21330545
Msx homeobox genes critically regulate embryo implantation by controlling paracrine signaling between uterine stroma and epithelium. [Nallasamy S, et al. PLoS Genet 2012;8(2):e1002500]
PubMed: 22383889
Use of kinase inhibitors to correct ΔF508-CFTR function. [Trzcinska-Daneluti AM, et al. Mol Cell Proteomics 2012;11(9):745-57]
PubMed: 22700489

Aquaporin3 Is Required for FGF-2-Induced Migration of Human Breast Cancers. [Cao XC, et al. PLoS One 2013;8(2), e56735]
PubMed: 23468877
L1CAM stimulates glioma cell motility and proliferation through the fibroblast growth factor receptor. [Mohanan V, et al. Clin Exp Metastasis 2012;ahead of print]
PubMed: 23212305

Tech Support & FAQs

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.

Handling Instructions

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BIBF1120 (Vargatef) is a potent inhibitor of VEGFR1/2/3, FGFR1/2/3 and PDGFRα/β with IC50 of 34 nM/13 nM/13 nM, 69 nM/37 nM/108 nM and 59 nM/65 nM, respectively.
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RTKs and Angiogenesis Related Products

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PD173074 + Cisplatin	In the H-510 xenograft, the anti-tumor effect of Cisplatin is significantly potentiated by coadministration of PD173074. ^[5]
PD173074 + Adriamycin	The combination of PD173074 with Paclitaxel or Doxorubicin shows synergistic activity in the FGFR2 mutant cell lines. ^[6]
PD173074 + Paclitaxel(Taxol)	The combination of PD173074 with Paclitaxel or Doxorubicin shows synergistic activity in the FGFR2 mutant cell lines. ^[6]

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PD173074 Licensed by Pfizer