title: Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity.
abstract: 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 model revealed strong reduction in staining of proliferation marker Ki-67 and phosphorylated extracellular regulated kinases 1/2. These data demonstrate that regorafenib is a well-tolerated, orally active multikinase inhibitor with a distinct target profile that may have therapeutic benefit in human malignancies.
authors.affiliation: Bayer HealthCare Pharmaceuticals, Montville, NJ, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Wilhelm
authors.forename: Jacques
authors.initials: J
authors.lastname: Dumas
authors.forename: Lila
authors.initials: L
authors.lastname: Adnane
authors.forename: Mark
authors.initials: M
authors.lastname: Lynch
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Carter
authors.forename: Gunnar
authors.initials: G
authors.lastname: Schütz
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Thierauch
authors.forename: Dieter
authors.initials: D
authors.lastname: Zopf
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D008279:Magnetic Resonance Imaging; D051379:Mice; D008819:Mice, Nude; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C559147:regorafenib