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Sci Rep. 2016 Mar 3;6:22450. doi: 10.1038/srep22450.

Small Molecule Inhibition of Ligand-Stimulated RAGE-DIAPH1 Signal Transduction.

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Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, 550 First Avenue, New York, 10016 New York, USA.
Department of Chemistry, University at Albany, State University of New York, 1400 Washington Avenue, Albany, 12222 New York, USA.
RJD Medicinal Chemistry and Drug Discovery Consulting LLC, 332 W. Dudley Avenue, Westfield, New Jersey 07090, USA.


The receptor for advanced glycation endproducts (RAGE) binds diverse ligands linked to chronic inflammation and disease. NMR spectroscopy and x-ray crystallization studies of the extracellular domains of RAGE indicate that RAGE ligands bind by distinct charge- and hydrophobicity-dependent mechanisms. The cytoplasmic tail (ct) of RAGE is essential for RAGE ligand-mediated signal transduction and consequent modulation of gene expression and cellular properties. RAGE signaling requires interaction of ctRAGE with the intracellular effector, mammalian diaphanous 1 or DIAPH1. We screened a library of 58,000 small molecules and identified 13 small molecule competitive inhibitors of ctRAGE interaction with DIAPH1. These compounds, which exhibit in vitro and in vivo inhibition of RAGE-dependent molecular processes, present attractive molecular scaffolds for the development of therapeutics against RAGE-mediated diseases, such as those linked to diabetic complications, Alzheimer's disease, and chronic inflammation, and provide support for the feasibility of inhibition of protein-protein interaction (PPI).

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