Small Molecule Inhibitors of KDR (VEGFR-2) Kinase: An Overview of Structure Activity Relationships

Abstract

The Kinase insert Domain containing Receptor (KDR), alternatively referred to as VEGFR-2, is a receptor for Vascular Endothelial Growth Factors (VEGFs) and functions as a key regulator of angiogenesis, the process by which new capillaries are created from preexisting blood vessels. The induction of angiogenesis, or the "angiogenic switch," is a critical step in tumor progression, and inhibitors of KDR have been demonstrated both to induce tumor regression and reduce metastatic potential in preclinical models. In the last few years, medicinal chemists have expanded the kinase selectivity profile of known inhibitor classes to include KDR, and also identified novel classes of KDR inhibitors. This review presents structure activity relationships (SAR) of small molecule inhibitors of KDR, with an emphasis on the pharmacophore elements of the scaffolds employed. Binding hypotheses based on X-ray crystallographic analyses will also be described. Additionally, the efficacy of representative compounds in in vitro and in vivo models of tumor progression and angiogenesis are discussed.

In vitro Procoagulant Activity Induced in Endothelial Cells by Chemotherapy and Antiangiogenic Drug Combinations: Modulation by Lower-Dose Chemotherapy

“…These drugs included ZD6474 and SU6668, both small-molecule VEGFR-2 antagonists (although neither is completely specific for VEGFR-2), the latter being a member of the same structural class of receptor tyrosine kinase inhibitors, such as SU5416 (i.e., an indolinone; ref. 29). Similarly, use of humanized monoclonal antibodies specific for human VEGFR-2 (IMC-1121) or VEGF (bevacizumab) was not associated with an increase in the coagulation index.…”

Increased Plasma Vascular Endothelial Growth Factor (VEGF) as a Surrogate Marker for Optimal Therapeutic Dosing of VEGF Receptor-2 Monoclonal Antibodies

“…At day 0 (i.e., before treatment) and each day after the injection until day 12 and later at days 15, 18, and 21, five or three mice per time point were anesthetized, bled, and sacrificed. Furthermore, to investigate a possible correlation between the administration of small molecule VEGFR-2 tyrosine kinase inhibitors and plasma mouse VEGF levels, SCID mice (6 -8 weeks old) were also treated with (a) 25 mg/kg/mouse SU5416 intraperitoneally (17,20) or vehicle alone (five mice per group) twice a week, and blood was collected at day 0 (before the treatment) and days 1, 4, 5, 8, and 12 after the beginning of the treatment; or (b) 50 mg/kg/mouse PTK787 (ref. 16; orally; by gavage; five mice per group) every day for 12 days, and blood was collected before treatment, 0.5 to 2 hour(s) after treatment, and from day 1 to day 21.…”

“…As a comparison with the DC101 antibody, PTK787 and SU5416, all synthetic (organic) small molecule antagonists of VEGFR-2 (20), were tested to determine whether any analogous increase in circulating mouse VEGF levels would be induced. From 0.5 hour to 21 days after the first PTK787 administration, no differences were detected (data not shown) between treated and untreated animals (ranging around the limit of detection of the ELISA kit).…”

The kinase insert domain-containing receptor is an angiogenesis-associated antigen recognized by human cytotoxic T lymphocytes

“…[15][16][17][18] It serves a key function during tumor angiogenesis: once bound to its ligand, VEGF, KDR mediates signals for the survival, proliferation, and differentiation of endothelial cells and for vascular permeability. 19 Such properties make KDR a valuable target for immunologic intervention.…”