title: A PDE6δ-KRas Inhibitor Chemotype with up to Seven H-Bonds and Picomolar Affinity that Prevents Efficient Inhibitor Release by Arl2.
abstract: Small-molecule inhibition of the interaction between the KRas oncoprotein and the chaperone PDE6δ impairs KRas spatial organization and signaling in cells. However, despite potent binding in vitro (KD<10 nm), interference with Ras signaling and growth inhibition require 5-20 μm compound concentrations. We demonstrate that these findings can be explained by fast release of high-affinity inhibitors from PDE6δ by the release factor Arl2. This limitation is overcome by novel highly selective inhibitors that bind to PDE6δ with up to 7 hydrogen bonds, resulting in picomolar affinity. Their release by Arl2 is greatly decreased, and representative compounds selectively inhibit growth of KRas mutated and -dependent cells with the highest activity recorded yet. Our findings indicate that very potent inhibitors of the KRas-PDE6δ interaction may impair the growth of tumors driven by oncogenic KRas.
authors.affiliation: Department of Chemical Biology, Max Planck Institute of Molecular Physiology, 44227, Dortmund, Germany.
authors.forename: Pablo
authors.initials: P
authors.lastname: Martín-Gago
authors.affiliation: Structural Biology Group, Max Planck Institute for Molecular Physiology, 44227, Dortmund, Germany.
authors.forename: Eyad K
authors.initials: EK
authors.lastname: Fansa
authors.affiliation: Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, 44227, Dortmund, Germany.
authors.forename: Christian H
authors.initials: CH
authors.lastname: Klein
authors.affiliation: Department of Chemical Biology, Max Planck Institute of Molecular Physiology, 44227, Dortmund, Germany.
authors.forename: Sandip
authors.initials: S
authors.lastname: Murarka
authors.affiliation: Department of Chemical Biology, Max Planck Institute of Molecular Physiology, 44227, Dortmund, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Janning
authors.affiliation: Department of Chemical Biology, Max Planck Institute of Molecular Physiology, 44227, Dortmund, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Schürmann
authors.affiliation: Department of Chemical Biology, Max Planck Institute of Molecular Physiology, 44227, Dortmund, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Metz
authors.affiliation: Structural Biology Group, Max Planck Institute for Molecular Physiology, 44227, Dortmund, Germany.
authors.forename: Shehab
authors.initials: S
authors.lastname: Ismail
authors.affiliation: Lead Discovery Center GmbH, 44227, Dortmund, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Schultz-Fademrecht
authors.affiliation: Lead Discovery Center GmbH, 44227, Dortmund, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Baumann
authors.affiliation: Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, 44227, Dortmund, Germany.|TU Dortmund, Faculty of Chemistry and Chemical Biology, 44227, Dortmund, Germany.
authors.forename: Philippe I H
authors.initials: PI
authors.lastname: Bastiaens
authors.affiliation: Structural Biology Group, Max Planck Institute for Molecular Physiology, 44227, Dortmund, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Wittinghofer
authors.affiliation: Department of Chemical Biology, Max Planck Institute of Molecular Physiology, 44227, Dortmund, Germany.|TU Dortmund, Faculty of Chemistry and Chemical Biology, 44227, Dortmund, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
keywords: PDEδ; Ras protein; drug design; medicinal chemistry; structure-activity relationships