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Perspectives on the discovery of NOTCH2‐specific inhibitors
Author(s) -
Dobranowski Peter,
Ban Fuqiang,
ContrerasSanz Alberto,
Cherkasov Artem,
Black Peter C.
Publication year - 2018
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13132
Subject(s) - notch signaling pathway , carcinogenesis , biology , notch proteins , computational biology , signal transduction , drug discovery , microbiology and biotechnology , epitope , intracellular , small molecule , structural similarity , extracellular , cancer research , gene , bioinformatics , biochemistry , genetics , antibody
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, NOTCH 1 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‐ NOTCH 2 antibody‐binding epitopes or the “S2‐Leu‐plug‐binding site” using a computer‐aided drug discovery approach.