Inhibition of angiogenesis via interference with VEGF signaling can in theory be achieved by multiple mechanisms, including: 1) direct blockade of VEGF binding to its receptor (VEGFR) by antagonists, such as soluble receptor analogs that sequester VEGF, anti-VEGFR antibodies and aptamers, and peptide or conventional small molecule drugs;  2) inhibition of the VEGF tyrosine receptor kinase (TRK);  3) inhibition of dimerization of VEGF, making it incapable of forming an active VEGFR dimer, 4) inhibition of dimerization of intracellular components of VEGFR so that an active TRK cannot be assembled. Of these, 1), 3) and 4) all require disruption of a protein-protein interaction. Identification of critical residues involved in recognition and binding at these protein-protein interfaces is key to an effective strategy for design of small molecule inhibitors. Using VEGF as a paradigm, we will review several approaches to the design of inhibitors that target protein-protein interactions critical for VEGFR signaling.

Approaches to the design of protein-protein interaction blockers targeting VEGF receptor signaling

244th National Meeting (2012)

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