Abstract |
Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor ( VEGF) signaling pathway is a new treatment modality in oncology. Preclinical findings suggest that blockade of additional pro-angiogenic kinases, such as fibroblast and platelet-derived growth factor receptors (FGFR and PDGFR), may improve the efficacy of pharmacological cancer treatment. Indolinones substituted in position 6 were identified as selective inhibitors of VEGF-, PDGF-, and FGF-receptor kinases. In particular, 6-methoxycarbonyl-substituted indolinones showed a highly favorable selectivity profile. Optimization identified potent inhibitors of VEGF-related endothelial cell proliferation with additional efficacy on pericyctes and smooth muscle cells. In contrast, no direct inhibition of tumor cell proliferation was observed. Compounds 2 ( BIBF 1000) and 3 ( BIBF 1120) are orally available and display encouraging efficacy in in vivo tumor models while being well tolerated. The triple angiokinase inhibitor 3 is currently in phase III clinical trials for the treatment of nonsmall cell lung cancer.
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Authors | Gerald J Roth, Armin Heckel, Florian Colbatzky, Sandra Handschuh, Jörg Kley, Thorsten Lehmann-Lintz, Ralf Lotz, Ulrike Tontsch-Grunt, Rainer Walter, Frank Hilberg |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 52
Issue 14
Pg. 4466-80
(Jul 23 2009)
ISSN: 1520-4804 [Electronic] United States |
PMID | 19522465
(Publication Type: Journal Article)
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Chemical References |
- Indoles
- Protein Kinase Inhibitors
- Receptors, Fibroblast Growth Factor
- Receptors, Platelet-Derived Growth Factor
- Vascular Endothelial Growth Factor Receptor-2
- nintedanib
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Topics |
- Administration, Oral
- Animals
- Carcinoma, Non-Small-Cell Lung
(drug therapy)
- Cell Line, Tumor
- Clinical Trials as Topic
- Drug Discovery
- Female
- Humans
- Indoles
(chemical synthesis, chemistry, pharmacology, therapeutic use)
- Inhibitory Concentration 50
- Lung Neoplasms
(drug therapy)
- Mice
- Protein Kinase Inhibitors
(analogs & derivatives, chemical synthesis, pharmacology, therapeutic use)
- Receptors, Fibroblast Growth Factor
(antagonists & inhibitors)
- Receptors, Platelet-Derived Growth Factor
(antagonists & inhibitors)
- Substrate Specificity
- Vascular Endothelial Growth Factor Receptor-2
(antagonists & inhibitors)
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