BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy.
Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a novel treatment modality in oncology. Preclinical findings suggest that long-term clinical outcomes may improve with blockade of additional proangiogenic receptor tyrosine kinases: platelet-derived growth factor receptors (PDGFR) and fibroblast growth factor receptors (FGFR). BIBF 1120 is an indolinone derivative potently blocking VEGF receptor (VEGFR), PDGFR and FGFR kinase activity in enzymatic assays (IC(50), 20-100 nmol/L). BIBF 1120 inhibits mitogen-activated protein kinase and Akt signaling pathways in three cell types contributing to angiogenesis, endothelial cells, pericytes, and smooth muscle cells, resulting in inhibition of cell proliferation (EC(50), 10-80 nmol/L) and apoptosis. In all tumor models tested thus far, including human tumor xenografts growing in nude mice and a syngeneic rat tumor model, BIBF 1120 is highly active at well-tolerated doses (25-100 mg/kg daily p.o.), as measured by magnetic resonance imaging of tumor perfusion after 3 days, reducing vessel density and vessel integrity after 5 days, and inducing profound growth inhibition. A distinct pharmacodynamic feature of BIBF 1120 in cell culture is sustained pathway inhibition (up to 32 hours after 1-hour treatment), suggesting slow receptor off-kinetics. Although BIBF 1120 is rapidly metabolized in vivo by methylester cleavage, resulting in a short mean residence time, once daily oral dosing is fully efficacious in xenograft models. These distinctive pharmacokinetic and pharmacodynamic properties may help explain clinical observations with BIBF 1120, currently entering phase III clinical development.
Hilberg
Frank
F
Boehringer Ingelheim Austria GmbH, Vienna, Austria and Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany. frank.hilberg@vie.boehringer-ingelheim.com
Roth
Gerald J
GJ
Krssak
Martin
M
Kautschitsch
Susanna
S
Sommergruber
Wolfgang
W
Tontsch-Grunt
Ulrike
U
Garin-Chesa
Pilar
P
Bader
Gerd
G
Zoephel
Andreas
A
Quant
Jens
J
Heckel
Armin
A
Rettig
Wolfgang J
WJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001779:Blood Coagulation Factors / Q000037:antagonists & inhibitors*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020286:Pericytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D001779:Blood Coagulation Factors; D004791:Enzyme Inhibitors; D007211:Indoles; D017468:Receptors, Fibroblast Growth Factor; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D017479:Receptors, Platelet-Derived Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2; C530716:nintedanib