title: E-3810 is a potent dual inhibitor of VEGFR and FGFR that exerts antitumor activity in multiple preclinical models.
abstract: Tumor angiogenesis is a degenerate process regulated by a complex network of proangiogenic factors. Existing antiangiogenic drugs used in clinic are characterized by selectivity for specific factors. Antiangiogenic properties might be improved in drugs that target multiple factors and thereby address the inherent mechanistic degeneracy in angiogenesis. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) family members and their cognate receptors are key players in promoting tumor angiogenesis. Here we report the pharmacologic profile of E-3810, a novel dual inhibitor of the VEGF and FGF receptors. E-3810 potently and selectively inhibited VEGF receptor (VEGFR)-1, -2, and -3 and FGF receptor (FGFR)-1 and -2 kinases in the nanomolar range. Ligand-dependent phosphorylation of VEGFR-2 and FGFR-1 was suppressed along with human vascular endothelial cell growth at nanomolar concentrations. In contrast, E-3810 lacked cytotoxic effects on cancer cell lines under millimolar concentrations. In a variety of tumor xenograft models, including early- or late-stage subcutaneous and orthotopic models, E-3810 exhibited striking antitumor properties at well-tolerated oral doses administered daily. We found that E-3810 remained active in tumors rendered nonresponsive to the general kinase inhibitor sunitinib resulting from a previous cycle of sunitinib treatment. In Matrigel plug assays performed in nude mice, E-3810 inhibited basic FGF-induced angiogenesis and reduced blood vessel density as assessed by histologic analysis. Dynamic contrast-enhanced magnetic resonance imaging analysis confirmed that E-3810 reduced the distribution of angiogenesis-sensitive contrast agents after only 5 days of treatment. Taken together, our findings identify E-3810 as a potent antiangiogenic small molecule with a favorable pharmacokinetic profile and broad spectrum antitumor activity, providing a strong rationale for its clinical evaluation.
authors.affiliation: Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, and E.O.S. S.p.A., Milan, Italy.
authors.forename: Ezia
authors.initials: E
authors.lastname: Bello
authors.forename: Gennaro
authors.initials: G
authors.lastname: Colella
authors.forename: Valentina
authors.initials: V
authors.lastname: Scarlato
authors.forename: Paolo
authors.initials: P
authors.lastname: Oliva
authors.forename: Alexander
authors.initials: A
authors.lastname: Berndt
authors.forename: Giovanni
authors.initials: G
authors.lastname: Valbusa
authors.forename: Sonia Colombo
authors.initials: SC
authors.lastname: Serra
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
authors.forename: Ennio
authors.initials: E
authors.lastname: Cavalletti
authors.forename: Raffaella
authors.initials: R
authors.lastname: Giavazzi
authors.forename: Giovanna
authors.initials: G
authors.lastname: Damia
authors.forename: Gabriella
authors.initials: G
authors.lastname: Camboni
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D005260:Female; D019073:HT29 Cells; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D064750:Rabeprazole; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D017468:Receptors, Fibroblast Growth Factor; D064750:Rabeprazole; D040262:Receptors, Vascular Endothelial Growth Factor