Delving into the Latest Updates on CGP-53716 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

CGP 53716

Target

PDGFR

Mechanism

PDGFR gene inhibitors

Therapeutic Areas

Neoplasms

Active Indication-

Inactive Indication

Neoplasms

Originator Organization

Novartis Pharma AG

Active Organization-

Inactive Organization

Novartis Pharma AG

Drug Highest PhasePendingPhase 1

First Approval Date-

Regulation-

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Structure

Molecular FormulaC23H19N5O

InChIKeyUOEJSOXEHKCNAE-UHFFFAOYSA-N

CAS Registry152459-94-4

Objective: To investigate the effects of tyrosine‐kinase inhibitors of vascular endothelial growth factor (VEGF) and platelet‐derived growth factor (PDGF)‐receptors on non‐malignant tissue and whether they depend upon the stage of vascular maturation.Materials and methods: PTK787/ZK222584 and CGP53716 (VEGF‐ and PDGF‐receptor inhibitor respectively), both alone and combined, were applied on chicken chorioallantoic membrane (CAM).Results: On embryonic day of CAM development (E)8, only immature microvessels, which lack coverage of pericytes, are present; whereas the microvessels on E12 have pericytic coverage. This development was reflected in the expression levels of pericytic markers (α ‐smooth muscle actin, PDGF‐receptor ß and desmin), which were found by immunoblotting to progressively increase between E8 and E12. Monotherapy with 2 μ g of PTK787/ZK222584 induced significant vasodegeneration on E8, but not on E12. Monotherapy with CGP53716 affected only pericytes. When CGP53716 was applied prior to treatment with 2 μ g of PTK787/ZK222584, vasodegeneration occurred also on E12. The combined treatment increased the apoptotic rate, as evidenced by the cDNA levels of caspase‐9 and the TUNEL‐assay.Conclusion: Anti‐angiogenic treatment strategies for non‐neoplastic disorders should aim to interfere with the maturation stage of the target vessels: monotherapy with VEGF‐receptor inhibitor for immature vessels, and combined anti‐angiogenic treatment for well developed mature vasculature.

01 Dec 2004·Journal of cancer research and clinical oncologyQ3 · MEDICINE

Signal transduction of c-Kit receptor tyrosine kinase in CHRF myeloid leukemia cells

Q3 · MEDICINE

Article

Author: Cornelia Kirsch ; Reinhard Klinger ; Sebastian Scholl ; Frank D. Böhmer

PURPOSE:

The tyrosine kinase receptor c-Kit (stem cell factor receptor, CD117) is a potential target for signal transduction therapy in different cancers. In this study we investigated c-Kit in CHRF cells, a megakaryoblastic cell line of Acute Myeloid Leukemia (FAB M7).

MATERIALS AND METHODS:

We characterized the interactions between c-Kit and PI 3-kinase (p85) after stimulation with SCF (stem cell factor) as well as the regulation of SHP-1 and SHP-2 associated with Kit in this cell line.

RESULTS:

Stimulation with SCF leads to a significant increase in interaction between Kit and p85 as well as in receptor associated PI 3-kinase activity. Interestingly, using different kinds of substances (AG 1295, CGP 53716) to inhibit the tyrosine kinase activity of c-Kit blocked activation of c-Kit, but the association of p85 still increased after SCF stimulation even when the tyrosine kinase activity of the receptor was completely blocked. In contrast, the other known interaction partners of c-Kit, SHP-1 and SHP-2, exhibited a basal association with c-Kit and no change of the association could be detected after stimulation of CHRF cells with SCF or treatment with the kinase inhibitors.

CONCLUSIONS:

Therefore, we suggest that association of p85, SHP-1, and SHP-2 to c-Kit in CHRF cells can, at least in part, occur in a c-Kit kinase-activity independent manner. In contrast, the kinase activity of c-Kit is necessary for the activation of receptor-associated PI 3-kinase.

01 Mar 2004·TransplantationQ2 · MEDICINE

Platelet-derived growth factor regulates cytomegalovirus infection-enhanced obliterative bronchiolitis in rat tracheal allografts

Q2 · MEDICINE

Article

Author: Bruggeman, Cathrien ; Krebs, Rainer ; Tikkanen, Jussi M. ; Koskinen, Petri K. ; Lemstrom, Karl B.

BACKGROUND:

Cytomegalovirus (CMV) infection is a risk factor for the development of obliterative bronchiolitis (OB) after lung transplantation.

METHODS:

In the rat tracheal allograft model, rat CMV (RCMV) infection is associated with accelerated OB through enhanced alloimmune activation and increased smooth muscle cell (SMC) proliferation. Using this model, we investigated the role of platelet-derived growth factor (PDGF) in RCMV infection-enhanced OB.

RESULTS:

Immunohistochemistry and in situ hybridization revealed that RCMV infection significantly up-regulates PDGF ligand and receptor expression in inflammatory and SMC-like cells in tracheal allografts. Selective inhibition of PDGF receptor tyrosine kinase activity by CGP 53716 prevents the development of OB in RCMV-infected allograft recipients.

CONCLUSION:

The results of this study emphasize the key regulatory role of PDGF in the pathogenesis of RCMV infection-enhanced OB, suggesting a novel strategy for the prevention of this fibroproliferative disorder.

100 Deals associated with CGP-53716

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