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Design, synthesis, and evaluation of indolinones as triple angiokinase inhibitors and the discovery of a highly specific 6-methoxycarbonyl-substituted indolinone (BIBF 1120).

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.
AuthorsGerald J Roth, Armin Heckel, Florian Colbatzky, Sandra Handschuh, Jörg Kley, Thorsten Lehmann-Lintz, Ralf Lotz, Ulrike Tontsch-Grunt, Rainer Walter, Frank Hilberg
JournalJournal of medicinal chemistry (J Med Chem) Vol. 52 Issue 14 Pg. 4466-80 (Jul 23 2009) ISSN: 1520-4804 [Electronic] United States
PMID19522465 (Publication Type: Journal Article)
Chemical References
  • Indoles
  • Protein Kinase Inhibitors
  • Receptors, Fibroblast Growth Factor
  • Receptors, Platelet-Derived Growth Factor
  • Vascular Endothelial Growth Factor Receptor-2
  • nintedanib
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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