title: Small Molecule Inhibition of Ligand-Stimulated RAGE-DIAPH1 Signal Transduction.
abstract: 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).
authors.affiliation: Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, 550 First Avenue, New York, 10016 New York, USA.
authors.forename: Michaele B
authors.initials: MB
authors.lastname: Manigrasso
authors.affiliation: Department of Chemistry, University at Albany, State University of New York, 1400 Washington Avenue, Albany, 12222 New York, USA.
authors.forename: Jinhong
authors.initials: J
authors.lastname: Pan
authors.affiliation: Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, 550 First Avenue, New York, 10016 New York, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Rai
authors.affiliation: Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, 550 First Avenue, New York, 10016 New York, USA.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, University at Albany, State University of New York, 1400 Washington Avenue, Albany, 12222 New York, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Reverdatto
authors.affiliation: Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, 550 First Avenue, New York, 10016 New York, USA.
authors.forename: Nosirudeen
authors.initials: N
authors.lastname: Quadri
authors.affiliation: RJD Medicinal Chemistry and Drug Discovery Consulting LLC, 332 W. Dudley Avenue, Westfield, New Jersey 07090, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: DeVita
authors.affiliation: Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, 550 First Avenue, New York, 10016 New York, USA.
authors.forename: Ravichandran
authors.initials: R
authors.lastname: Ramasamy
authors.affiliation: Department of Chemistry, University at Albany, State University of New York, 1400 Washington Avenue, Albany, 12222 New York, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Shekhtman
authors.affiliation: Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, 550 First Avenue, New York, 10016 New York, USA.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Schmidt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D006801:Humans; D051379:Mice; D000067759:Receptor for Advanced Glycation End Products / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000593873:Ager protein, mouse; D000067759:Receptor for Advanced Glycation End Products