Wednesday, October 7, 2015

Drugs in Clinical Pipeline: Foretinib | EXEL-2880 | HGF, VEGF Inhibitor | Multi-Kinase Inhibitor | Angiogenesis Inhibitor

Foretinib [N-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide] is a small-molecule kinase inhibitor that targets members of the HGF and VEGF receptor tyrosine kinase families, with additional inhibitory activity toward KIT, Flt-3, platelet-derived growth factor receptor β, and Tie-2. Binding of Foretinib to Met and VEGF receptor 2 (KDR) is characterized by a very slow off-rate, consistent with X-ray crystallographic data showing that the inhibitor is deeply bound in the Met kinase active site cleft [1].

Foretinib: 2D and 3D Structure

Foretinib inhibits cellular HGF-induced Met phosphorylation and VEGF-induced extracellular signal-regulated kinase phosphorylation and inhibits growth of tumor cells under both normoxic and hypoxic conditions with increased potency against Met-amplified gastric cancer cell lines. In vitroForetinib inhibits HGF-induced responses of tumor cells and HGF/VEGF-induced responses of endothelial cells that are thought to contribute to invasion, metastasis, and angiogenesis in vivo. Consistent with this profile, Foretinib inhibits tumor formation in an in vivo murine model of lung metastasis. Foretinib therefore has the potential to prevent tumor growth through a direct effect on tumor cell proliferation and indirectly through inhibition of the host angiogenic response.

Using high-throughput unbiased screening approach to identify small-molecule kinase inhibitors with potent activity against orphan RTK c-ros oncogene 1 (ROS1), researchers found that Foretinib is a highly effective inhibitor of ROS1 in human and murine model systems, demonstrating greater potency compared with Crizotinib both in vitro and in vivo. Despite the reported binding affinity (Kd) of Crizotinib for ROS1 being lower than that of Foretinib (4.4 nM and 14 nM, respectively), researchers found Foretinib to be a significantly more potent ROS1 inhibitor in cell-based assays, accentuating that the in vitro binding affinity does not directly translate to inhibitory efficacy in the cellular context.

Exelixis is credited with discovering Foretinib. It was called EXEL-2880 at Exelixis. Subsequently, the compound was licensed to GlaxoSmithKline in December 2007 where it was called GSK1363089. It is in Phase II trials for various cancers.

The activity of Foretinib is as follows:

IC50 (Met enzyme assay) = 0.4 ± 0.04 nM
IC50 (Ron enzyme assay) = 3 ± 0.2 nM
IC50 (KDR enzyme assay) = 0.86 ± 0.04 nM
IC50 (Flt-1 enzyme assay) = 6.8 ± 0.7 nM
IC50 (Flt-4 enzyme assay) = 2.8 ± 0.4 nM
IC50 (KIT enzyme assay) = 6.7 ± 0.6 nM
IC50 (Flt-3 enzyme assay) = 3.6 ± 0.4 nM
IC50 (PDGFR-α enzyme assay) = 3.6 ± 0.4 nM
IC50 (PDGFR-β enzyme assay) = 9.6 ± 1.1 nM
IC50 (Tie-2 enzyme assay) = 1.1 ± 0.1 nM
IC50 (FGFR1 enzyme assay) = 660 ± 50 nM
IC50 (EGFR enzyme assay) = 2990 ± 38 nM

Common Name: Foretinib
Synonyms: XL880; XL 880; XL-880; EXEL-2880; GSK1363089; GSK 1363089; GSK-1363089; SK1363089; GSK089
IUPAC Name: N-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
CAS Number: 849217-64-7
Mechanism of Action: Kinase Inhibitor; Multi-Kinase Inhibitor; MET Kinase Inhibitor; KDR Inhibitor
Indication: Various Cancers; Anti-tumor Agents; Angiogenesis Inhibitor
Development Stage: Phase II
Company: Exelixis Inc/GlaxoSmithKline

1H NMR (Estimated) for Foretinib

1. Qian, F.; et. al. Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. Cancer Res 2009, 69(20), 8009-8016.