Design, synthesis, and evaluation of indolinones as triple angiokinase inhibitors and the discovery of a highly specific 6-methoxycarbonyl-substituted indolinone (BIBF 1120).
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.
Roth
Gerald J
GJ
Department of Chemical Research, Boehringer Ingelheim Pharma GmbH &Co KG, D-88397 Biberach, Germany.
Heckel
Armin
A
Colbatzky
Florian
F
Handschuh
Sandra
S
Kley
Jörg
J
Lehmann-Lintz
Thorsten
T
Lotz
Ralf
R
Tontsch-Grunt
Ulrike
U
Walter
Rainer
R
Hilberg
Frank
F
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*
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