title: Direct Modulation of Small GTPase Activity and Function.
abstract: Small GTPases are a family of GDP-/GTP-binding proteins that serve as biomolecular switches inside cells to control a variety of essential cellular processes. Aberrant function and regulation of small GTPases is associated with a variety of human diseases, thus rendering these proteins highly interesting targets in drug discovery. However, this class of proteins has been considered "undruggable", as intensive decade-long efforts did not yield clinically relevant direct modulators of small GTPases. Recently, the targeting of small GTPases has gained fresh impetus through the discovery of novel transient cavities on the protein surfaces and the application of new targeting strategies. Besides Ras proteins, other small GTPases have attracted increased attention since improved biological insight in combination with novel targeting strategies identified them as promising targets in drug discovery. This Review gives an overview of relevant aspects of the superfamily of small GTPases and summarizes recent progress and perspectives for the direct modulation of these challenging targets.
authors.affiliation: Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany).|Technical University Dortmund, Department of Chemistry and Chemical Biology, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany).
authors.forename: Philipp M
authors.initials: PM
authors.lastname: Cromm
authors.affiliation: Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany).|Technical University Dortmund, Department of Chemistry and Chemical Biology, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany).
authors.forename: Jochen
authors.initials: J
authors.lastname: Spiegel
authors.affiliation: Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany). tom.grossmann@cgc.mpg.de.|Technical University Dortmund, Department of Chemistry and Chemical Biology, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany). tom.grossmann@cgc.mpg.de.|Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Strasse 15, 44227 Dortmund (Germany). tom.grossmann@cgc.mpg.de.
authors.forename: Tom N
authors.initials: TN
authors.lastname: Grossmann
authors.affiliation: Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany). herbert.waldmann@mpi-dortmund.mpg.de.|Technical University Dortmund, Department of Chemistry and Chemical Biology, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany). herbert.waldmann@mpi-dortmund.mpg.de.
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
mesh_terms: D006801:Humans; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D020559:Monomeric GTP-Binding Proteins
keywords: cancer; drug design; inhibitors; proteins; small GTPases