The development of a VEGF-receptor antagonist, VGA115

Angiogenesis, the formation of new blood vessels, is crucial to a number of physiological processes such as reproduction, development and tissue repair, as well as in disease states including cancer, rheumatoid arthritis (see LeadDiscovery’s recent report ”Rheumatoid arthritis: Emerging drug discovery targets and therapeutic candidates”) and other inflammatory diseases. Consequently angiogenesis represents an emerging therapeutic target which by 2006, is expected to command a market of $1.75 billion.

Tumor vascularization is key to the development of solid tumors and the vast majority of pharmaceutical activity surrounding angiogenesis relates to the development of therapeutic strategies to destroy existing tumor vasculature or to prevent neovascularization. Despite early enthusiasm for angiogenesis inhibitors as safe and effective anticancer drugs, several Phase III and Phase II trials have proved disappointing. Newer strategies are however being developed which will hopefully confer greater efficacy to this field (for an analysis of pharmaceutical activity surrounding the development of angiogenesis inhibitors click here).

Although there are multiple opportunities for the development of anti-angiogenic molecules, the most advanced targets are the growth factors. The principal growth factors driving angiogenesis include VEGF, a homodimeric 45kDa glycoprotein that specifically acts on endothelial cells binding to endothelial tyrosine kinase receptors including Flt-1 (VEGFR-1) and KDR/flk-1 (VEGFR-2). Activation of VEGF receptors promotes endothelial cell growth, mitogenesis, and tube formation.

Prior to their acquisition by Pfizer earlier last year, one of the leaders in the field of angiogenesis therapeutics was the San Francisco biotech, SUGEN. SU11248 is one inhibitor of angiogenesis that emerged from SUGEN’s pipeline. This orally active small molecule inhibits the kinase activity of Flk-1/KDR, as well as PDGFR, a further growth factor receptor involved in tumor angiogenesis. SU11248 has previously been shown to have broad and potent antitumor activity in mice, decreasing tumor microvessel density and tumor cell proliferation and increasing tumor cell apoptosis, culminating in tumor regression.

As an alternative to VEGF kinase inhibition blocking the binding of VEGF to these receptors may also be of therapeutic benefit. In their recent Molecular Cancer Therapeutics paper, researchers at Taisho Pharmaceuticals in collaboration with Ikuo Saiki report the activity of VGA1155. This molecule was identified by high throughput screening of Taishi’s library against VEGFR-1. Subsequent studies demonstrated that VGA115 antagonized the binding of VEGF to both VEGF-1 and –2 receptors with IC50 values of 380 and 140nM respectively. This activity resulted from binding to the receptors rather than to VEGF, and produced functional antagonism since VGA1155 inhibited VEGF-induced receptor tyrosine autophosphorylation. VGA1155 was selective in that it did not affect the binding of a variety of other ligands to their receptors. One of the functional effects of VEGF is to increase vascular permeability and in a further experiment, VGA1155 was found to inhibit this activity.

To our knowledge VGA1155 is one of the first small molecule antagonists of VEGF-1 and –2 and contrasts with molecules such as SU11248 which inhibit the kinase activity of these receptors. This functional difference may confer significant advantages and further testing of VGA1155 in models of cancer is therefore eagerly awaited.

Entry date Thursday, January 22, 2004

Adapted from Ueda et al, Mol Cancer Ther. 2003 Nov; 2(11): 1105-11.