FIGURE 2.

Mechanistic basis for therapeutic targeting of ligand-specific Notch signaling. Agents targeting Notch signaling can be grouped by the step or process in the Notch signaling pathway that is being affected. Soluble decoys comprise of extracellular portions of Notch ligands or receptors that can competitively inhibit multivalent receptor-ligand interactions. Soluble multivalent ligands comprise of clustered ligands that provide and/or augment ligand-specific Notch activation. Blocking antibodies block receptor interactions with ligands and are paralog-specific antagonists with high selectivity. γ-secretase inhibitors prevent NICD release by inhibiting S3 cleavage of Notch receptors at the juxtamembrane domain. L-fucose analogs (solid red triangles) are taken up by cells from media and incorporated into receptor extracellular domains. Fucose analogs on Notch receptors alter ligand-binding affinities and can be used to block selective ligand interactions. Blocking peptides target protein-protein interface in the nuclear Notch transcriptional complex and prevent transcription of Notch target genes. In vitro, pre-clinical and clinical studies demonstrating Notch-modulatory activities and anti-tumor efficacy of various classes of Notch therapeutics are presented in Table 1.