Antiangiogenic Agents: an Update on Small Molecule VEGFR Inhibitors

Abstract

Angiogenesis is a tightly regulated process that leads to the formation of new blood vessels sprouting from pre-existing microvasculature and occurs in limited physiological conditions or under pathological situations such as retinopathies, arthritis, endometriosis and cancer. Blockade of angiogenesis is an attractive approach for the treatment of such diseases. Particularly in malignancies, antiangiogenic therapy should be less toxic in comparison with conventional treatments such as chemotherapy, as angiogenesis is a process relatively restricted to the growing tumor. Vascular endothelial growth factor (VEGF) is one of the most important inducers of angiogenesis and exerts its cellular effects mainly by interacting with two high-affinity transmembrane tyrosine kinase receptors: VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). It has been proven that inhibition of VEGF receptor activity reduces angiogenesis. For these reasons, the inhibition of VEGF or its receptor signalling system is an attractive target for therapeutic intervention. The most studied and developed inhibitors are monoclonal antibodies that neutralize VEGF, ribozymes, and small molecule VEGFR kinase inhibitors. Many important reviews dealing with VEGF-induced angiogenesis and its inhibition through the block of VEGF receptors have been reported, especially from a biological point of view. Here, we will review small synthetic VEGFR inhibitors that have appeared in literature in the last few years, focusing our attention on their medicinal chemistry in terms of chemical structure, mechanisms of action and structure-activity relationships. In fact, there have been an increased number of tyrosine kinase inhibitors in the most recent literature reports; their biological profile is extremely interesting and could be of great importance to medicinal chemists working in this area in improving their efficacy.

Discovery of Dual VEGFR-2 and Tubulin Inhibitors with in Vivo Efficacy

“…VEGFR-2 cellular potency was further improved to submicromolar levels by substituting a pyridine central core for the benzene ring. Structure-activity relationship trends similar to the benzo [1,3]dioxol-5-yl subseries were also observed within the 2,3-dihydro-benzo-[1,4]dioxin-6-yl subclass (compare 9-13 to 14, 16, and 18-20, respectively). Heterocyclic groups other than the 4-pyridyl moiety likewise showed dual kinase/tubulin activity within the 2,3-dihydro-benzo [1,4]dioxin-6-yl subclass (imidazolyl 21 and quinolinyl 23).…”

“…8 This work demonstrated that a trifluoromethyl group in the meta position in compound 1 or benzo [1,3]dioxol-5-yl functionality in triazole 4 results in an inhibitory activity in the VEGFR-2 enzymatic assay (Table 1). Moreover, triazole 1 along with several other analogues (not shown) exhibited VEGFR-2 activity around 1 μM in the cellular phosphorylation assay.…”

“…VEGF binding to the receptor tyrosine kinase VEGFR-2, located on the surface of endothelial cells, induces trans-phosphorylation and dimerization of the receptor. 3 This results in increased migration and proliferation of endothelial cells as well as enhanced permeability of the surrounding vasculature. Inhibiting the kinase activity of VEGFR-2 or blocking VEGF binding to its receptor has become an effective approach in treating cancer.…”

“…The trifluoromethyl group on the phenyl moiety that had previously provided us with VEGFR-2 activity ( Table 1) resulted in a loss of tubulin potency in both tubulin polymerization and G 2 M block assays. Therefore, we focused on the benzo [1,3]dioxol-5-yl (piperonyl) group of analogue 4 since we had described the tubulin activity of piperonylcontaining compounds in our earlier work on tubulin active scaffolds. 6,7 We reasoned that the addition of a 4-pyridyl group, a common element of multiple VEGFR-2 active classes, [8][9][10] would lend VEGFR-2 activity to our compounds.…”

“…A breakthrough in our effort to introduce both VEGFR-2 kinase and tubulin activities simultaneously came from a substitution of the benzo [1,3]dioxol-5-yl functionality with the closely related 2,3-dihydro-benzo [1,4]dioxin-6-yl group ( Table 2). This group was shown to improve tubulin properties.…”