Inhibition of FGF-1 Receptor Tyrosine Kinase Activity by Pd 161570, a New Protein-Tyrosine Kinase Inhibitor

Batley, Brian L.; Doherty, Annette M.; Hamby, James M.; Lu, Gina H.; Keller, Paul R.; Dahring, Tawny K.; Hwang, Ok Jin; Crickard, Kent; Panek, Robert L.

doi:10.1016/s0024-3205(97)01060-6

Cited by 20 publications

(26 citation statements)

References 32 publications

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“…Here, we investigated the effects of two compounds, Axitinib and PD-161,570, which have shown to be growth factor selective and anti-angiogenic both in vitro and in vivo. [15][16][17][18] Axitinib is currently used in the clinic for treatment of patients with renal cell carcinoma who have failed to respond to other interventions. Using our in vitro model, axitinib treatment in the presence of VEGF potently inhibited VEGF-mediated angiogenesis (Fig.…”

Section: Correlations Between In Vitro Results and In Vivo Pharmacologymentioning

confidence: 99%

“…Notably, a compound exhibiting this type of selectivity may be important clinically in such diseases as diabetic retinopathy, atherosclerosis, and tumor neovascularization, in which abnormal FGF receptor expression has been implicated in disease progression. 17 In addition to showing growth factor selectivity for small-molecule inhibitors, it was important to demonstrate that not all tyrosine kinase inhibitors are active in this model. Lestaurtinib, a potent JAK2, FLT3, and TrkA inhibitor that exhibits antiproliferative activity in vitro and is used for myeloproliferative disorders in vivo, has not been shown to be active in affecting angiogenesis.…”

Section: Correlations Between In Vitro Results and In Vivo Pharmacologymentioning

confidence: 99%

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Pharmacologic Characterization of a Kinetic In Vitro Human Co-Culture Angiogenesis Model Using Clinically Relevant Compounds

et al. 2013

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Angiogenesis, the formation of new vessels from preexisting vessels, involves multiple cell types acting in concert to cause endothelial cell proliferation, migration, and differentiation into microvascular arrays. Under pathologic conditions, microenvironment changes result in altered blood vessel production. Historically, in vitro angiogenesis assays study individual aspects of the process and tend to be variable, difficult to quantify, and limited in clinical relevance. Here, we describe a kinetic, quantitative, co-culture angiogenesis model and demonstrate its relevance to in vivo pharmacology. Similar to in vivo angiogenesis, a co-culture of human umbilical vein endothelial cells with normal human dermal fibroblasts remains sensitive to multiple cytokines, resulting in a concentration-dependent stimulation of tube formation over time. Treatment with axitinib, a selective vascular endothelial growth factor (VEGF) antagonist, inhibited VEGF-mediated tube length and branch point formation and was selective for inhibiting VEGF over basic fibroblast growth factor (bFGF), similar to previous studies. Conversely, an FGFR-1 selective compound, PD-161570, was more potent at inhibiting bFGF-mediated angiogenesis. These results demonstrate the cytokine dynamics, selective pharmacology, and translational application of this model system. Finally, combining quantitative angiogenic biology with kinetic, live-content imaging highlights the importance of using validated in vitro models in drug discovery research.

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Section: Correlations Between In Vitro Results and In Vivo Pharmacologymentioning

confidence: 99%

Section: Correlations Between In Vitro Results and In Vivo Pharmacologymentioning

confidence: 99%

Pharmacologic Characterization of a Kinetic In Vitro Human Co-Culture Angiogenesis Model Using Clinically Relevant Compounds

et al. 2013

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“…PD161570 is an FGFR tyrosine kinase inhibitor 54, while PD173074 has been described to inhibit FGFR1 and FGFR3 80.…”

Section: Type V Rtks: Fgf (Fibroblast Growth Factor) Receptor Familymentioning

confidence: 99%

The Concise Guide to PHARMACOLOGY 2013/14: Catalytic Receptors

Alexander

Benson

Faccenda

et al. 2013

British J Pharmacology

151

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The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full.Catalytic receptors are one of the seven major pharmacological targets into which the Guide is divided, with the others being G protein-coupled receptors, ligand-gated ion channels, ion channels, nuclear hormone receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets.It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors and Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and the Guide to Receptors and Channels, providing a permanent, citable, point-in-time record that will survive database updates.

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“…In rat aortic smooth muscle cells, PDGFR autophosphorylation was blocked at an IC 50 of 450 nM. In addition, the constitutive phosphorylation of the FGF-1R was suppressed with an IC 50 between 450 and 670 nM [44,45,47]. Replacement of the 2,6-dichlorophenyl substituent by a 3,5-dimethoxyphenyl moiety controlled selectivity with respect to the FGFR kinase as shown for compound 33 (PD 166866) which had an IC 50 value of 60 nM against this kinase but did not inhibit the PDGFR, c-Src, MAP, CDK4, EGFR and IR kinases.…”

Section: Pyrido-pyrimidines and Pyrimido-pyrimidinesmentioning

confidence: 99%

Tyrosine kinase inhibitors in cancer treatment (Part II)

Traxler

1998

Expert Opinion on Therapeutic Patents

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In the last few years, enormous progress in the field of signal transduction inhibition has been made. Many companies have entered the field. Along with the epidermal growth factor receptor (EGFR) tyrosine kinase, many other tyrosine kinases have been identified as interesting targets for drug discovery projects. X-ray data of more than 40 crystal structures of protein kinases, in most cases complexed with an inhibitor, have been published. Pharmacophore models for the binding of inhibitors in the ATP-binding site of protein kinases have been developed that are generally applicable, enabling the rational design of tyrosine as well as serine/threonine kinase inhibitors. It has been proven by numerous examples that the ATP-binding of protein kinases is an exciting target for the design of anticancer drugs. In many cases, it has also been demonstrated that through rational design it is possible to modify a lead structure in such a way that inhibitors with an altered selectivity profile are obtained. Chemical optimisation of several lead structures led to development candidates with potent in vitro and in vivo activity fulfilling the pharmacodynamic, pharmacokinetic, toxicological and technical (synthesis, formulation) requirements for a clinical candidate. Currently, there are seven tyrosine kinase inhibitors in early phases of clinical trials. In addition, several candidates are close to entering Phase I trials this year or at the beginning of next year. It is expected that positive results from clinical trials will greatly contribute to the clinical proof of concept of the value of signal transduction inhibition and will greatly stimulate further research in this area. This review is a continuation of a review with the same title of last year and summarises published patent literature and related publications between 1997 and September 1998.

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Inhibition of FGF-1 Receptor Tyrosine Kinase Activity by Pd 161570, a New Protein-Tyrosine Kinase Inhibitor

Cited by 20 publications

References 32 publications

Pharmacologic Characterization of a Kinetic In Vitro Human Co-Culture Angiogenesis Model Using Clinically Relevant Compounds

Pharmacologic Characterization of a Kinetic In Vitro Human Co-Culture Angiogenesis Model Using Clinically Relevant Compounds

The Concise Guide to PHARMACOLOGY 2013/14: Catalytic Receptors

Tyrosine kinase inhibitors in cancer treatment (Part II)

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