PD173074

 PD173074

Distributor Tel: +886-2-2827-1197jimmy@new.abscience.com.tw

Biological Activity

Description	PD173074 is a potent FGFR1 inhibitor with IC50 of ~25 nM and also inhibits VEGFR2 with IC50 of 100-200 nM, ~1000-fold selective for FGFR1 than PDGFR and c-Src.
Targets	FGFR1	VEGFR2
IC50	~25 nM	100-200 nM [1]
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]
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
Dosages	~2 mg/kg/day
Administration	Administered intraperitoneally

1

References

Chemical Information

Download PD173074 SDF

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

Preparing Stock Solutions

Stock Solution (1ml DMSO)	1mM	10mM	20mM	30mM
Mass(mg)	0.52367	5.2367	10.4734	15.7101

Customer Reviews (2)

Click to enlarge	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.

Product Citations (8)

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  The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2. [Li Q, et al. Science 2011;331(6019):912-6]

  
  PubMed: 21330545


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  Identification of Targetable FGFR Gene Fusions in Diverse Cancers. [Wu YM, et al. Cancer Discov 2013;3(6):636-47]

  
  PubMed: 23558953


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  Ponatinib overcomes FGF2-mediated resistance in CML patients without kinase domain mutations. [Traer E, et al. Blood 2013;10.1182/blood-2013-07-518381 ]

  
  PubMed: 24408322