PD 173074

FGFR inhibitor CAS# 219580-11-7

PD 173074

Catalog No. BCC3662----Order now to get a substantial discount!

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Chemical structure

PD 173074

3D structure

Chemical Properties of PD 173074

Cas No. 219580-11-7 SDF Download SDF
PubChem ID 1401 Appearance Powder
Formula C28H41N7O3 M.Wt 523.67
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : ≥ 52 mg/mL (99.30 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name 1-tert-butyl-3-[2-[4-(diethylamino)butylamino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]urea
SMILES CCN(CC)CCCCNC1=NC2=NC(=C(C=C2C=N1)C3=CC(=CC(=C3)OC)OC)NC(=O)NC(C)(C)C
Standard InChIKey DXCUKNQANPLTEJ-UHFFFAOYSA-N
Standard InChI InChI=1S/C28H41N7O3/c1-8-35(9-2)13-11-10-12-29-26-30-18-20-16-23(19-14-21(37-6)17-22(15-19)38-7)25(31-24(20)32-26)33-27(36)34-28(3,4)5/h14-18H,8-13H2,1-7H3,(H3,29,30,31,32,33,34,36)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of PD 173074

DescriptionSelective FGFR1 and FGFR3 inhibitor (IC50 values are 5, 21.5, ~100, 17600 and 19800 nM for FGFR3, FGFR1, VEGFR2, PDGFR and c-Src respectively, and > 50000 nM for EGFR, InsR, MEK and PKC). Inhibits VEGF- and FGF-induced angiogenesis in the mouse cornea model of angiogenesis. Inhibits proliferation and differentiation of oligodendrocyte progenitors. Suppresses cell proliferation in cell lines expressing mutated FGFR3 protein. Blocks tumor growth in H510 and H69 SCLC xenograft models.

PD 173074 Dilution Calculator

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PD 173074 Molarity Calculator

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Preparing Stock Solutions of PD 173074

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.9096 mL 9.548 mL 19.096 mL 38.192 mL 47.74 mL
5 mM 0.3819 mL 1.9096 mL 3.8192 mL 7.6384 mL 9.548 mL
10 mM 0.191 mL 0.9548 mL 1.9096 mL 3.8192 mL 4.774 mL
50 mM 0.0382 mL 0.191 mL 0.3819 mL 0.7638 mL 0.9548 mL
100 mM 0.0191 mL 0.0955 mL 0.191 mL 0.3819 mL 0.4774 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on PD 173074

PD173074 is a poten and selective fibroblast growth factor receptor (FGFR) inhibitor. Fibroblast growth factor-2 is reported to be able to induce proliferation and chemoresistance in Small cell lung cancer (SCLC) cells.

In vitro: PD173074 was found to block H-510 and H-69 SCLC proliferation and clonogenic growth in a dose-dependent fashion and prevent FGF-2-induced chemoresistance as well. These effects correlate with the inhibition of both FGFR1 and FGFR2 transphosphorylation. In addition, PD173074 showed a high degree of selectivity for FGFR tyrosine kinase [2].

In vivo: In the H-510 xenograft mouse model, tumor growth was significanlty improved similar to that seen with single-agent cisplatin administration. Accordingly, PD173074 treatment resulted in significanlty prolonged median survival when compared with that of control sham-treated animals. More dramatically, PD173074 also induced complete responses lasting >6 months in 50% of in mice H-69 xenografts [2].

Clinical trial: PD173074 is still in the preclinical development stage, and no clinical data are available currently.

References:
[1] Pardo OE, Latigo J, Jeffery RE, Nye E, Poulsom R, Spencer-Dene B, Lemoine NR, Stamp GW, Aboagye EO, Seckl MJ.  The fibroblast growth factor receptor inhibitor PD173074 blocks small cell lung cancer growth in vitro and in vivo. Cancer Res. 2009 Nov 15;69(22):8645-51.
[2] Mohammadi M, Froum S, Hamby JM, Schroeder MC, Panek RL, Lu GH, Eliseenkova AV, Green D, Schlessinger J, Hubbard SR.  Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain. EMBO J. 1998 Oct 15;17(20):5896-904.

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References on PD 173074

The FGFR1 inhibitor PD 173074 selectively and potently antagonizes FGF-2 neurotrophic and neurotropic effects.[Pubmed:10987832]

J Neurochem. 2000 Oct;75(4):1520-7.

Basic fibroblast growth factor (FGF-2) promotes survival and/or neurite outgrowth from a variety of neurons in cell culture and regenerative processes in vivo. FGFs exert their effects by activating cell surface receptor tyrosine kinases. FGF receptor (FGFR) inhibitors have not been characterized on neuronal cell behaviors to date. In the present study, we show that the FGFR1 inhibitor PD 173074 potently and selectively antagonized the neurotrophic and neurotropic actions of FGF-2. Nanomolar concentrations of PD 173074 prevented FGF-2, but not insulin-like growth factor-1, support of cerebellar granule neuron survival under conditions of serum/K(+) deprivation; another FGF-2 inhibitor, SU 5402, was effective only at a 1,000-fold greater concentration. Neither PD 173074 nor SU 5402, at 100 times their IC(50) values, interfered with the survival of dorsal root ganglion neurons promoted by nerve growth factor, ciliary neurotrophic factor, or glial cell line-derived neurotrophic factor. PD 173074 and SU 5402 displayed 1,000-fold differential IC(50) values for inhibition of FGF-2-stimulated neurite outgrowth in PC12 cells and in granule neurons, and FGF-2-induced mitogen-activated protein kinase (p44/42) phosphorylation. The two inhibitors failed to disturb downstream signalling stimuli of FGF-2. PD 173074 represents a valuable tool for dissecting the role of FGF-2 in normal and pathological nervous system function without compromising the actions of other neurotrophic factors.

1-tert-butyl-3-[6-(3,5-dimethoxy-phenyl)-2-(4-diethylamino-butylamino)-pyrido[2,3 -d]pyrimidin-7-yl]-urea (PD173074), a selective tyrosine kinase inhibitor of fibroblast growth factor receptor-3 (FGFR3), inhibits cell proliferation of bladder cancer carrying the FGFR3 gene mutation along with up-regulation of p27/Kip1 and G1/G0 arrest.[Pubmed:19955487]

J Pharmacol Exp Ther. 2010 Mar;332(3):795-802.

Activating mutation of the fibroblast growth factor receptor-3 (FGFR3) gene is known as a key molecular event in both oncogenesis and cell proliferation of low-grade noninvasive human bladder urothelial carcinoma (UC), which is characterized by frequent intravesical recurrence. In this study, we investigated the antitumor potentiality of 1-tert-butyl-3-[6-(3,5-dimethoxy-phenyl)-2-(4-diethylamino-butylamino)-pyrido[2,3 -d]pyrimidin-7-yl]-urea (PD173074), a small-molecule FGFR3-selective tyrosine kinase inhibitor (TKI), as a therapeutic modality using eight UC cell lines. In our in vitro cell proliferation assay, PD173074 suppressed cell proliferation remarkably in two cell lines, namely, UM-UC-14 and MGHU3, which expressed mutated FGFR3 protein. In contrast, the other six cell lines expressing wild-type FGFR3 or without FGFR3 expression were resistant to PD173074 treatment. Cell cycle analysis revealed the growth inhibitory effect of PD173074 was associated with arrest at G(1)-S transition in a dose-depending manner. Furthermore, we observed an inverse relationship between Ki-67 and p27/Kip1 expression after PD173074 treatment, suggesting that up-regulation of p27 recruited UC cells harboring activating FGFR3 mutations in G(1) that was analogous with the other receptor TKIs acting on the epidermal growth factor receptors. In the mouse xenograft models using subcutaneously transplanted UM-UC-14 and MGHU3, orally administered PD173074 suppressed tumor growth and induced apoptotic changes comparable with the results of our in vitro assay. These findings elucidated the effectiveness of molecular targeted approach for bladder UC harboring FGFR3 mutations and the potential utility to decrease the intravesical recurrence of nonmuscle invasive bladder UC after transurethral surgical resection.

Specific inhibitor of FGF receptor signaling: FGF-2-mediated effects on proliferation, differentiation, and MAPK activation are inhibited by PD173074 in oligodendrocyte-lineage cells.[Pubmed:14598292]

J Neurosci Res. 2003 Nov 15;74(4):486-93.

Multiple studies have shown that migration, proliferation, and differentiation of oligodendrocyte (OL) lineage cells are influenced by fibroblast growth factor-2 (FGF-2) signaling through its receptors (FGFR) FGFR-1, FGFR-2, and FGFR-3. We report the effectiveness and specificity of a unique inhibitor, PD173074, for inhibiting FGF receptor signaling in OL-lineage cells. Three FGF-mediated responses of OL progenitors and two of differentiated OLs were examined by immunofluorescence microscopy and immunoblotting. PD173074 effectively antagonized the effect of FGF-2 on proliferation and differentiation of OL progenitors in culture. One dose of PD173074 at nanomolar concentrations was sufficient to inhibit ongoing FGF-2 mediated proliferation for prolonged periods, in a non-toxic, dose-dependent manner. In contrast, platelet-derived growth factor (PDGF)-induced proliferation was unaffected by PD173074. Similarly, mitogen-activated protein kinase (MAPK) activation, a downstream event after activation of either FGFR or PDGFR, was also blocked by PD173074 in OL progenitors stimulated with FGF-2 but not PDGF. A general tyrosine kinase inhibitor (PD166285), however, antagonized both FGF-2- and PDGF-mediated responses. PD173074 also completely antagonized two phenotypic alterations of differentiated OLs, specifically downregulation of myelin proteins, and their re-entry into the cell cycle. We conclude that PD173704 is an effective and specific inhibitor for multiple FGF-2-mediated responses of both OL progenitors and differentiated OLs. This inhibitor provides a direct approach for identifying the importance of FGF signaling, comparable in effect to a knockout of all FGF receptors and all FGF ligands, while leaving other pathways unaffected. Thus, PD173704 is an excellent tool for investigating the role of FGF signaling in vivo in the context of combinatorial interactions of other signals.

Description

PD173074 is a potent FGFR1 inhibitor with an IC50 of 25 nM and also inhibits VEGFR2 with an IC50 of 100-200 nM, showing 1000-fold selectivity for FGFR1 over PDGFR and c-Src.

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