Perspectives on the discovery of NOTCH2-specific inhibitors

Abstract

The Notch pathway is a cell-cell communication system where membrane-bound ligands interact with the extracellular region of Notch receptors to induce intracellular, downstream effects on gene expression. Aberrant Notch signaling promotes tumorigenesis, and the Notch pathway has tremendous potential for novel targeting strategies in cancer treatment. While γ-secretase inhibitors as Notch-inhibiting agents are already promising in clinical trials, they are highly non-specific with adverse side effects. One of the underlying challenges is that two of the four known human Notch paralogs, NOTCH1 and 2, share very high structural similarity but play opposing roles in some tumorigenesis pathways. This perspective explores the feasibility of developing Notch-specific small molecule inhibitors targeting the anti-NOTCH2 antibody binding epitopes or the 'S2-Leu plug-binding site' using a computer-aided drug discovery approach.

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We review current Notch inhibitors of small molecules and expensive monoclonal antibodies.

Our computational modeling of the Notch proteins suggests that the S2 cleavage site, blocked by a conserved Leucine residue in the receptor's inactive state, is a plausible Notch-specific therapeutic site to target.

Synthetic antibody mimics present an attractive future drug modality to target specific Notch paralogs and replace monoclonal antibodies.

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