Regorafenib (BAY 73‐4506): A new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity
Open accessAbstract
Angiogenesis, a critical driver of tumor development, is controlled by interconnected signaling pathways. Vascular endothelial growth factor receptor (VEGFR) 2 and tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 play crucial roles in the biology of normal and tumor vasculature. Regorafenib (BAY 73-4506), a novel oral multikinase inhibitor, potently inhibits these endothelial cell kinases in biochemical and cellular kinase phosphorylation assays. Furthermore, regorafenib inhibits additional angiogenic kinases (VEGFR1/3, platelet-derived growth factor receptor-β and fibroblast growth factor receptor 1) and the mutant oncogenic kinases KIT, RET and B-RAF. The antiangiogenic effect of regorafenib was demonstrated in vivo by dynamic contrast-enhanced magnetic resonance imaging. Regorafenib administered once orally at 10 mg/kg significantly decreased the extravasation of Gadomer in the vasculature of rat GS9L glioblastoma tumor xenografts. In a daily (qd)×4 dosing study, the pharmacodynamic effects persisted for 48 hr after the last dosing and correlated with tumor growth inhibition (TGI). A significant reduction in tumor microvessel area was observed in a human colorectal xenograft after qd×5 dosing at 10 and 30 mg/kg. Regorafenib exhibited potent dose-dependent TGI in various preclinical human xenograft models in mice, with tumor shrinkages observed in breast MDA-MB-231 and renal 786-O carcinoma models. Pharmacodynamic analyses of the breast mode…
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Direct inhibition of MAPK signaling has posed therapeutic challenges due to adverse effects including retinal toxicity, increased risk of retinal fibrosis, photoreceptor degeneration, and impaired RPE function.
“However, direct inhibition of MAPK signaling has posed therapeutic challenges due to associated adverse effects 39,40 , including retinal toxicity, increased risk of retinal fibrosis, photoreceptor degeneration, and impaired retinal pigment epithelium (RPE) function, necessitating the development of alternative therapeutic strategies.”
From rAAV-mediated Multi-miRNA Delivery Targeting MAPK Pathway Suppresses Laser-induced Choroidal Neovascularization in Mice (2026) · cites this paper as [40]
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- Authors
- Wilhelm, S. M., Dumas, J., Adnane, L., Lynch, M., Carter, C. A., Schütz, G., Thierauch, K., & Zopf, D.
- Affiliations
- Bayer (Germany) (DE)
- Corresponding author
- Zopf, Dieter
- Venue
- International Journal of Cancer
- Publisher
- Wiley
- Published
- 2011-04-22
- Volume
- 129
- Issue
- 1
- Pages
- 245-255
- ISSN
- 0020-7136 (ISSN-L)
- 1097-0215
- OpenAlex
- W1968209756
- Cited by
- 1,355
- References
- 1
- Citations by year
- 2026: 67 · 2025: 72 · 2024: 104 · 2023: 98 · 2022: 116 · 2021: 130 · 2020: 122 · 2019: 111 · 2018: 95 · 2017: 93 · 2016: 81 · 2015: 71 · 2014: 87 · 2013: 66 · 2012: 32
- FWCI
- 14.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- International Journal of Cancer (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
- Keywords
- regorafenib, multikinase inhibitor, angiogenesis, VEGFR2, VEGFR1, VEGFR-3, PDGFRβ, FGFR1, KIT, RET, BRAF, tumor microvessel density, glioblastoma, colorectal cancer, breast cancer, renal cell carcinoma, tumor xenografts, Ki-67, ERK1/2 phosphorylation, anticancer activity, pharmacodynamics
- MeSH terms
- Animals, Antineoplastic Agents, Enzyme Inhibitors, Female, Magnetic Resonance Imaging, Mice, Nude, Phenylurea Compounds, Phosphorylation, Pyridines, Rats, Inbred F344, Angiogenesis Inhibitors, Protein Kinase Inhibitors, Cell Proliferation, Mice, Rats
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