Development of Vascular Endothelial Growth Factor Receptor (VEGFR) Kinase Inhibitors as Anti-Angiogenic Agents in Cancer Therapy

Abstract

Among the known angiogenic growth factors and cytokines implicated in the modulation of normal and pathological angiogenesis, the VEGF family (VEGF-A, VEGF-B, VEGF-C, VEGF-D) and their corresponding receptor tyrosine kinases [VEGFR-1 (Flt-1), VEGFR-2 (Flk-1, KDR), and VEGFR-3 (Flt-4)] play a paramount and indispensable role in regulating the multiple facets of the angiogenic and lymphangiogenic processes, as well as the induction of vascular permeability and inflammation. The receptor VEGFR-2/KDR is the principal one through which VEGFs exert their mitogenic, chemotactic, and vascular permeabilizing effects on the host vasculature. Increased expression of VEGFs by tumor cells and VEGFR-2/KDR and VEGFR-1/Flt-1 by the tumor-associated vasculature are a hallmark of a variety of human and rodent tumors in vivo and correlates with tumor growth rate, micro-vessel density/proliferation, tumor metastatic potential, and poorer patient prognosis in a variety of malignancies. Approaches to disrupting the VEGF/VEGFR signaling cascade range from biological agents (soluble receptors, anti-VEGF and anti-VEGFR-2 antibodies, and VEGF transcription inhibitors) to small molecule ATP competitive VEGFR inhibitors. Examples from this latter class that are currently in clinical development include compounds from distinct chemical classes such as: indolin-2-ones, anilinoquinazolines, anilinophthalazines, isothiazoles, indolo- and indenocarbazoles. The structure activity relationships, biochemical and pharmacological profile of optimized representatives from each of these classes constitute the subject matter of this review.

Potential autocrine function of vascular endothelial growth factor in head and neck cancer via vascular endothelial growth factor receptor-2

“…A fundamental approach to inhibit angiogenesis during tumorigenesis is the disruption of VEGF/VEGFR-2 pathway. 41 This could suppress tumor growth by limiting their blood supply, by changing the morphology, wall structure and function of tumor vasculature to a more normal fashion, 42 and thus improving drug penetration in tumors, and also by blocking VEGF autocrine pathway and thus reducing uncontrolled neoplastic cell proliferation.…”

“…41 The most studied is SU5416 (semaxanib), which also presents inhibitory activity towards VEGFR-1. Studies in mice with transgenic prostate adenocarcinoma (TRAMP model) 43 revealed a significant decrease in intratumor microvessel density, an increment in cancer cell's apoptotic index, and pronounced regions of cell death.…”

Specificity landscapes of DNA binding molecules elucidate biological function

“…Here, we focused on the CSI-SSL scores of a hairpin polyamide (PA-4) that targets the binding sites of the hypoxia induced transcription factor, HIF-1α. PA-4 binding to HIF-responsive-elements (HREs) blocks the activation of the hypoxia induced genes (18), including VEGF, a cytokine that is implicated in cancer and angiogenesis (43). Blocking HIF-1α dependent expression of VEGF suffices for averting tumorigenesis, thus marking this binding event as a target for therapeutic intervention.…”

Pharmacological Abrogation of S-Phase Checkpoint Enhances the Anti-Tumor Activity of Gemcitabine In Vivo

“…Notably, two of the most potently inhibited kinases were KDR (VEGFR-2, IC 50 = 12 nM) and Flt-4 (VEGFR-3, IC 50 = 6 nM), two receptor tyrosine kinases that are implicated in survival and development of tumor vasculature and which have also attracted much attention as potential targets for therapeutic intervention. 19 Effects of EXEL-9844 on Cdc25A induction and Chk1 activation. Previous studies have shown that treatment of cells with gemcitabine induces Chk1 and Chk2 phosphorylation.…”