BIBF 1120: Triple Angiokinase Inhibitor with Sustained Receptor Blockade and Good Antitumor Efficacy

Hilberg, Frank; Roth, Gerald J.; Krssak, Martin; Kautschitsch, Susanna; Sommergruber, Wolfgang; Tontsch-Grunt, Ulrike; Garin-Chesa, Pilar; Bader, Gerd; Zoephel, Andreas; Quant, Jens; Heckel, Armin; Rettig, Wolfgang J.

doi:10.1158/0008-5472.can-07-6307

Cited by 1,056Angiogenesis and VEGF in CancerLymphatic System and DiseasesSynthesis and biological activity

BIBF 1120: Triple Angiokinase Inhibitor with Sustained Receptor Blockade and Good Antitumor Efficacy

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Hilberg, Frank, Roth, Gerald J., Krssak, Martin, Kautschitsch, Susanna, Sommergruber, Wolfgang, Tontsch-Grunt, Ulrike, Garin-Chesa, Pilar, Bader, Gerd +4 more·2008·Cancer Research

DOI 10.1158/0008-5472.can-07-6307

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Abstract

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 (IC50, 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 (EC50, 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. [Cancer Res 2008;68(12):4774–82]

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Increased Ezh2 expression and β-cell BrdU incorporation from PDGF-AA are eliminated by simultaneous treatment with Sunitinib or Vargatef.
“Increased Ezh2 expression and β-cell BrdU incorporation were eliminated by simultaneous treatment with the receptor tyrosine kinase inhibitors Sunitinib20 or Vargatef21 (Supplementary Fig. 4a, c, g, h).”
From PDGF signalling controls age-dependent proliferation in pancreatic β-cells (2011) · cites this paper as [21]

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Authors: Hilberg, F., Roth, G. J., Krssak, M., Kautschitsch, S., Sommergruber, W., Tontsch-Grunt, U., Garin-Chesa, P., Bader, G., Zoephel, A., Quant, J., Heckel, A., & Rettig, W. J.
Affiliations: Boehringer Ingelheim (Austria) (AT)
Boehringer Ingelheim (Germany) (DE)
1Boehringer Ingelheim Austria GmbH, Vienna, Austria and
ORCID: Hilberg, Frank
Tontsch-Grunt, Ulrike
Bader, Gerd
Zoephel, Andreas
Quant, Jens
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2008-06-15
Volume: 68
Issue: 12
Pages: 4774-4782
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-07-6307
OpenAlex: W2089756110
Cited by: 1,056
References: 48
Citations by year: 2026: 24 · 2025: 45 · 2024: 71 · 2023: 68 · 2022: 73 · 2021: 72 · 2020: 61 · 2019: 61 · 2018: 72 · 2017: 82 · 2016: 79 · 2015: 106 · 2014: 69 · 2013: 43 · 2012: 38
FWCI: 12.74
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Cancer Research (publishedVersion)
PubMed (publishedVersion)
DORA PSI (Paul Scherrer Institute) (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
Keywords: nintedanib, angiogenesis inhibitors, VEGF receptors, PDGFR, fibroblast growth factor receptor, indolinones, antitumor efficacy, tumor xenografts, pharmacokinetics, MAPK signaling, Akt signaling, tumor perfusion, oral administration
MeSH terms: Animals, Blood Coagulation Factors, Cells, Cultured, Endothelium, Vascular, Enzyme Inhibitors, Female, Humans, Indoles, Mice, Nude, Neoplasms, Experimental, Rats, Inbred F344, Tissue Distribution, Molecular Structure, Signal Transduction, Apoptosis, Receptors, Fibroblast Growth Factor, Receptors, Platelet-Derived Growth Factor, Pericytes, Xenograft Model Antitumor Assays, Myocytes, Smooth Muscle, Vascular Endothelial Growth Factor Receptor-2, Vascular Endothelial Growth Factor A, Cell Proliferation, Mice, Rats

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