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Inhibitors of protein kinases: CGP 41251, a protein kinase inhibitor with potential as an anticancer agent
D Fabbro1, E Buchdunger, J Wood
1Department of Oncology, Novartis Pharma Inc., Basel, Switzerland.
Abstract:
CGP 41251 was originally identified as an inhibitor of protein kinase C (PKC), inhibiting mainly the conventional PKC subtypes, and subsequently shown to inhibit the vascular endothelial growth factor (VEGF) receptor kinase insert domain-containing receptor, which is involved in angiogenesis. CGP 41251 inhibits reversibly intracellular PKC activity, induction of c-fos and the corresponding activation of the mitogen-activated protein kinase induced by either tumor promoting phorbol esters, platelet-derived growth factor, or basic fibroblast growth factor, but not by the epidermal growth factor. CGP 41251 inhibited the ligand-induced autophosphorylation of the receptors for platelet-derived growth factor, stem cell factor, and VEGF (kinase insert domain-containing receptor) that correlated with the inhibition of the mitogen-activated protein kinase activation, but did not affect the ligand-induced autophosphorylation of the receptors for insulin, insulin-like growth factor-I, or epidermal growth factor. CGP 41251 showed broad antiproliferative activity against various tumor and normal cell lines in vitro, and is able to reverse the p-glycoprotein-mediated multidrug resistance of tumor cells in vitro. CGP 41251 showed in vivo antitumor activity as single agent and inhibited angiogenesis in vivo. Thus, CGP 41251 may suppress tumor growth by inhibiting tumor angiogenesis (via its effects on the VEGF receptor tyrosine kinases) in addition to directly inhibiting tumor cell proliferation (via its effects on PKCs).
Insights
CGP 41251, an inhibitor of protein kinase C (PKC) and vascular endothelial growth factor (VEGF) receptor, demonstrates significant antitumor effects. It suppresses tumor growth by inhibiting both cancer cell proliferation and angiogenesis.
Area of Science:
- Pharmacology
- Molecular Biology
- Cancer Research
Background:
- Protein kinase C (PKC) and vascular endothelial growth factor (VEGF) receptor signaling pathways are crucial in cell proliferation and angiogenesis.
- CGP 41251 is a known inhibitor of PKC, with subsequent identification as an inhibitor of VEGF receptor kinase.
Purpose of the Study:
- To investigate the molecular mechanisms and therapeutic potential of CGP 41251 in cancer.
- To evaluate the effects of CGP 41251 on PKC and VEGF receptor signaling, cell proliferation, multidrug resistance, and angiogenesis.
Main Methods:
- In vitro assays measuring intracellular PKC activity, c-fos induction, mitogen-activated protein kinase (MAPK) activation, and receptor autophosphorylation.
- In vitro assessment of antiproliferative activity and reversal of p-glycoprotein-mediated multidrug resistance.
- In vivo studies evaluating antitumor activity and inhibition of angiogenesis.
Main Results:
- CGP 41251 reversibly inhibited intracellular PKC activity and MAPK activation induced by specific growth factors, but not epidermal growth factor.
- CGP 41251 inhibited ligand-induced autophosphorylation of platelet-derived growth factor, stem cell factor, and VEGF receptors, correlating with MAPK inhibition.
- The compound exhibited broad antiproliferative activity in vitro, reversed multidrug resistance, and demonstrated in vivo antitumor activity and angiogenesis inhibition.
Conclusions:
- CGP 41251 suppresses tumor growth through dual mechanisms: direct inhibition of tumor cell proliferation via PKC inhibition and inhibition of tumor angiogenesis via VEGF receptor tyrosine kinase inhibition.
- These findings highlight CGP 41251 as a potential therapeutic agent for cancer, targeting key pathways involved in tumor growth and development.