Perspectives on the discovery of NOTCH2-specific inhibitors

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. This article is protected by copyright. All rights reserved.

Chemical biology & drug design. 2017 Oct 27 [Epub ahead of print]

Peter Dobranowski, Fuqiang Ban, Alberto Contreras-Sanz, Artem Cherkasov, Peter C Black

Department of Pediatrics, British Columbia Children's Hospital Research, The University of British Columbia, Vancouver, British Columbia, Canada, 950 W 28th Ave, Vancouver, BC, V5Z 4H4., Department of Urologic Sciences, Faculty of Medicine, Vancouver Prostate Centre, The University of British Columbia, Vancouver, British Columbia, Canada.


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