title: 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.
authors.affiliation: Department of Chemical Research, Boehringer Ingelheim Pharma GmbH &Co KG, D-88397 Biberach, Germany.
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Roth
authors.forename: Armin
authors.initials: A
authors.lastname: Heckel
authors.forename: Florian
authors.initials: F
authors.lastname: Colbatzky
authors.forename: Sandra
authors.initials: S
authors.lastname: Handschuh
authors.forename: Jörg
authors.initials: J
authors.lastname: Kley
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lehmann-Lintz
authors.forename: Ralf
authors.initials: R
authors.lastname: Lotz
authors.forename: Ulrike
authors.initials: U
authors.lastname: Tontsch-Grunt
authors.forename: Rainer
authors.initials: R
authors.lastname: Walter
authors.forename: Frank
authors.initials: F
authors.lastname: Hilberg
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D055808:Drug Discovery; D005260:Female; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D013379:Substrate Specificity; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D017468:Receptors, Fibroblast Growth Factor; D017479:Receptors, Platelet-Derived Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2; C530716:nintedanib