title: Allosteric IGF-1R Inhibitors.
abstract: Targeting allosteric protein sites is a promising approach to interfere selectively with cellular signaling cascades. We have discovered a novel class of allosteric insulin-like growth factor-I receptor (IGF-1R) inhibitors. 3-Cyano-1H-indole-7-carboxylic acid {1-[4-(5-cyano-1H-indol-3-yl)butyl]piperidin-4-yl}amide (10) was found with nanomolar biochemical, micromolar, cellular IGF-1R activity and no relevant interference with cellular insulin receptor signaling up to 30 μM. The allosteric binding site was characterized by X-ray crystallographic studies, and the structural information was used to explain the unique mode of action of this new class of inhibitors.
authors.affiliation: Merck Serono, Frankfurter Strasse 250, 64293 Darmstadt, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Heinrich
authors.affiliation: Merck Serono, Frankfurter Strasse 250, 64293 Darmstadt, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Grädler
authors.affiliation: Merck Serono, Frankfurter Strasse 250, 64293 Darmstadt, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Böttcher
authors.affiliation: Merck Serono, Frankfurter Strasse 250, 64293 Darmstadt, Germany.
authors.forename: Andree
authors.initials: A
authors.lastname: Blaukat
authors.affiliation: EMD Serono Research Institute, One Technology Place, Rockland, Massachusetts 02370.
authors.forename: Adam
authors.initials: A
authors.lastname: Shutes
keywords: IGF-1R; allosteric inhibition; indole-butyl-amine; kinase inhibitor