Discovery of Potent Vascular Endothelial Growth Factor Receptor‐2 Inhibitors

Abstract

Substantial evidence over the last decades has implicated uncontrolled angiogenesis with various pathological states, including cancer. Vascular endothelial growth factor (VEGF) plays a critical role in its regulation. Because the tyrosine kinase VEGF receptor-2 (VEGFR-2) is the major mediator of the mitogenic, angiogenic, and permeability-enhancing effects of VEGF, it has become one of the most profound anti-angiogenesis targets. Inspired by the anthranilamide class of VEGFR-2 inhibitors, we performed a computational analysis of some potent representative members, using docking and molecular dynamics calculations. Based on the observations drawn from introducing the effect of the receptor's flexibility in implicit aqueous environment, we designed, synthesized, and characterized several new analogues of related scaffolds with modifications in their steric and electronic characteristics. In vitro evaluation of these compounds revealed several novel VEGFR-2 inhibitors that are less cytotoxic and more potent than the parent compounds.

A ZebrafishIn VivoPhenotypic Assay to Identify 3-Aminothiophene-2-Carboxylic Acid-Based Angiogenesis Inhibitors

“…29,30 From the previously identified potent VEGFR2 inhibitors [1] (IC 50 = 3 nM), [2] (IC 50 < 1 nM), and [3] (IC 50 = 70 nM), only the parent compound (ALL993) and compound [1] displayed reversible suppression of angiogenesis > 75% at 10 mM ( Table 1). 15 Based on these results, a new series of thiophene-based analogues were designed based on either [1] with Ar 1 = 3-pyridine or ALL993…”

“…1), a highly potent and selective inhibitor of VEGFRs with good pharmacological properties and excellent oral bioavailability, we designed and synthesized a small library of inhibitors for VEGFR2. 15 Several examples from that work, analogues [1][2][3] shown in Figure 1, demonstrated exceptional binding affinities for VEGFR2. 15 Stimulated by the successful outcome of these efforts, we decided to enrich our chemical library with additional examples and expand our analysis to include their evaluation in vivo.…”

“…15 Several examples from that work, analogues [1][2][3] shown in Figure 1, demonstrated exceptional binding affinities for VEGFR2. 15 Stimulated by the successful outcome of these efforts, we decided to enrich our chemical library with additional examples and expand our analysis to include their evaluation in vivo. Herein, we report the design, synthesis, and in vivo biological evaluation of 60 new analogues based on 3-aminothiophene-2-carboxylic acid, which resulted in the identification of 6 novel molecules with antiangiogenic properties.…”

“…15 Specifically, methyl-3-aminothiophene-2-carboxylate [4] was hydrolyzed with KOH at 120°C producing quantitatively the corresponding amino acid [5]. The reaction needs to be instantaneously heated at that temperature otherwise decarboxylated by-products may be obtained.…”

Recent Advances in Antiangiogenic Agents with VEGFR as Target

“…The hydrophobic group of inhibitors is accommodated within a lipophilic pocket defined by residues Ile 888, Leu 889, Ile 898, Val 899, Leu 1019, and Ile 1044, while the phenyl ring is sandwiched between the hydrophobic side chain components of Val 914 and Lys 868 ( Fig. 1) [18].…”