Vascular Endothelial Growth Factor Receptor Kinase 2 (VGFR-2) Focused Library

Among the known angiogenic growth factors and cytokines implicated in the modulation of normal and pathological angiogenesis, the VEGF family and their corresponding receptor tyrosine kinases (VEGFR-1, VEGFR-2, and VEGFR-3) play a paramount and indispensable role in regulating multiple facets of the angiogenic and lymphangiogenic processes as well as in induction of vascular permeability and inflammation [1]. The receptor VEGFR-2 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 by the tumor-associated vasculature is a hallmark of a variety of human and rodent tumors in vivo and correlates with tumor growth rate, microvessel 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 stage include compounds from distinct chemical classes.

The Life Chemicals VGFR-2 Focused Library comprises potential VEGFR-2 type II inhibitors that could bind to kinase in DFG-out conformation of the activation loop. Type-II kinase inhibitors have several advantages over type-I kinase inhibitors, including improved kinase selectivity and slower off-rates. Therefore, we focused on identification of putative type-II VEGFR kinase inhibitors. For this aim we have created a docking model of the protein based on crystal structure recorded in 3VHE PDB entry [2]. The key amino acids, responsible for hydrogen bonding of the ligand, were set to Cys919 from the hinge region, and also conserved Glu885 and Asp1046. Two hydrophobic regions of the binding site of VEGFR-2 were identified and included in the docking constraints: the first one was created by DFG-out conformational rearrangement of Phe1047 and the second was an extended hydrophobic pocket formed within Ile892, Leu1019, Phe1018. Molecular docking and subsequent analysis of its results were performed with DOCK4.0-6.0 program. Molecular dynamics (MD) simulation and preparation of protein structures were carried out with GROMACS software. Ligand molecules were processed with GAMESS and GROMACS. Only the compounds satisfying Lipinski and Veber Rules were selected for docking screening.

In this library, more than 1,000 stock available compounds were identified as virtual hits.

References

  1. Underiner TL, Ruggeri B, Gingrich DE. Development of vascular endothelial growth factor receptor (VEGFR) kinase inhibitors as anti-angiogenic agents in cancer therapy. Curr Med Chem, 2004, 11(6), 731-745.
  2. Oguro, Y. et. al. Design, synthesis, and evaluation of 5-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine derivatives: novel VEGFR2 kinase inhibitors binding to inactive kinase conformation. Bioorg.Med.Chem., 2010, 18, pp 7260– 7273.