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 welltolerated 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. Cancer Res; 71(4); 1396-405. Ó2011 AACR.

FGFR a promising druggable target in cancer: Molecular biology and new drugs

“…A notable array of compounds have been described in recent years to (partially) inhibit FGFR, next to other Tyrosine Kinase Receptor (TKR), including Vascular Endothelial Growth Factor Receptor (VEGFR), Platelet Derived Growth Factor Receptor (PDGFR), Fms-like tyrosine kinase 3 (FLT-3), c-Kit (c-KIT), Rearranged during transfection (RET) and BCR-ABL. These compounds include Brivatinib (Cai et al, 2008), Lenvatinib (Yamamoto et al, 2014), Regorafenib (Wilhelm et al, 2011), Ponatinib (Gozgit et al, 2012), Dovitininb (Porta et al, 2015), Nintedanib (Dhillon, 2015), Pazopanib (Prince et al, 2009), Orantinib (Ohta et al, 2009), ENMD 2076 (Matulonis et al, 2013), Lucitanib (Bello et al, 2011), PBI 05204 (Hong et al, 2014), Sunitinib (Welti et al, 2011) and Cediranib (Wedge et al, 2005). Although some of them have achieved approval for use against several cancer types, this section only focuses on those multi-target inhibitors that have included a subset of patients with FGFR alterations (Table 1).…”

Newly discovered angiogenesis inhibitors and their mechanisms of action

“…(2) Marine-derived compounds could be another important source of angiogenesis inhibitors, and certain compounds with specific types of chemical structures, such as saccharides, should be subjected to particular scrutiny; as demonstrated by JG3 [27] and GLP [30] , these compounds may exhibit unique modes of antiangiogenic activity. (3) Chemical synthesis, particularly if it is based on rational designs and modifications, is a common, frequently necessary method of generating compounds with possible medical applications; this principle is demonstrated by AL3810 in this instance [11,31] (Table 1) can be used as chemical models for further modification and optimization to improve their therapeutic potential as angiogenesis-inhibiting drugs for clinical use. (5) The known primary target(s) of certain compounds, such as pseudolaric acid B [15,16,18] and MFTZ-1 [17] , are not necessarily related to their antiangiogenic effects, indicating that unknown and potentially novel mechanism(s) are involved in these effects; these mechanisms merit further investigation.…”

“…Several of these PTKs, including VEGFR, PDGFR, and FGFR1, have been demonstrated to contribute to tumor angiogenesis [11,31] . In recent years, we have discovered hundreds of compounds with inhibitory activities against different PTKs and have reported that 9 compounds exhibit potent antiangio- genic effects (Table 1).…”

“…In recent years, we have discovered hundreds of compounds with inhibitory activities against different PTKs and have reported that 9 compounds exhibit potent antiangio- genic effects (Table 1). Of these 9 compounds, AL3810 (also designated as E-3810) [31] demonstrates the greatest potential for clinical use.…”

“…AL3810 is a synthetic multitargeted PTK inhibitor that inhibits VEGFR1, VEGFR2, PDGFRα, PDGFRβ, and FGFR1 with IC 50 values in the nanomolar range [11,31] . In endothelial cells, AL3810 can suppress the autophosphorylation of VEGFR2, PDGFRβ and FGFR1.…”