title: A Pan-GTPase Inhibitor as a Molecular Probe.
abstract: Overactive GTPases have often been linked to human diseases. The available inhibitors are limited and have not progressed far in clinical trials. We report here a first-in-class small molecule pan-GTPase inhibitor discovered from a high throughput screening campaign. The compound CID1067700 inhibits multiple GTPases in biochemical, cellular protein and protein interaction, as well as cellular functional assays. In the biochemical and protein interaction assays, representative GTPases from Rho, Ras, and Rab, the three most generic subfamilies of the GTPases, were probed, while in the functional assays, physiological processes regulated by each of the three subfamilies of the GTPases were examined. The chemical functionalities essential for the activity of the compound were identified through structural derivatization. The compound is validated as a useful molecular probe upon which GTPase-targeting inhibitors with drug potentials might be developed.
authors.affiliation: Department of Pathology, University of New Mexico, Albuquerque, New Mexico, United States of America; University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, United States of America.
authors.forename: Lin
authors.initials: L
authors.lastname: Hong
authors.affiliation: Department of Pathology, University of New Mexico, Albuquerque, New Mexico, United States of America.
authors.forename: Yuna
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Pathology, University of New Mexico, Albuquerque, New Mexico, United States of America.
authors.forename: Soumik
authors.initials: S
authors.lastname: BasuRay
authors.affiliation: Department of Pathology, University of New Mexico, Albuquerque, New Mexico, United States of America.
authors.forename: Jacob O
authors.initials: JO
authors.lastname: Agola
authors.affiliation: Department of Pathology, University of New Mexico, Albuquerque, New Mexico, United States of America.
authors.forename: Elsa
authors.initials: E
authors.lastname: Romero
authors.affiliation: University of Kansas Specialized Chemistry Center, Lawrence, Kansas, United States of America.
authors.forename: Denise S
authors.initials: DS
authors.lastname: Simpson
authors.affiliation: University of Kansas Specialized Chemistry Center, Lawrence, Kansas, United States of America.
authors.forename: Chad E
authors.initials: CE
authors.lastname: Schroeder
authors.affiliation: Department of Pathology, University of New Mexico, Albuquerque, New Mexico, United States of America; University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Simons
authors.affiliation: Department of Pathology, University of New Mexico, Albuquerque, New Mexico, United States of America; University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, United States of America.
authors.forename: Anna
authors.initials: A
authors.lastname: Waller
authors.affiliation: Department of Pathology, University of New Mexico, Albuquerque, New Mexico, United States of America; University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, United States of America.
authors.forename: Matthew
authors.initials: M
authors.lastname: Garcia
authors.affiliation: Department of Pathology, University of New Mexico, Albuquerque, New Mexico, United States of America; University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Carter
authors.affiliation: University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, United States of America; Cancer Research and Treatment Center, University of New Mexico, Albuquerque, New Mexico, United States of America; Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, New Mexico, United States of America.
authors.forename: Oleg
authors.initials: O
authors.lastname: Ursu
authors.affiliation: Department of Pathology, University of New Mexico, Albuquerque, New Mexico, United States of America; University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, United States of America.
authors.forename: Kristine
authors.initials: K
authors.lastname: Gouveia
authors.affiliation: University of Kansas Specialized Chemistry Center, Lawrence, Kansas, United States of America.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Golden
authors.affiliation: University of Kansas Specialized Chemistry Center, Lawrence, Kansas, United States of America; Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas, United States of America.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Aubé
authors.affiliation: Department of Pathology, University of New Mexico, Albuquerque, New Mexico, United States of America; Cancer Research and Treatment Center, University of New Mexico, Albuquerque, New Mexico, United States of America.
authors.forename: Angela
authors.initials: A
authors.lastname: Wandinger-Ness
authors.affiliation: Department of Pathology, University of New Mexico, Albuquerque, New Mexico, United States of America; University of New Mexico Center for Molecular Discovery, Albuquerque, New Mexico, United States of America; Cancer Research and Treatment Center, University of New Mexico, Albuquerque, New Mexico, United States of America.
authors.forename: Larry A
authors.initials: LA
authors.lastname: Sklar
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D016023:Integrins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D015335:Molecular Probes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020298:U937 Cells; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins; D018631:ras Proteins / Q000378:metabolism
chemical_list: C000607523:CID1067700; D004791:Enzyme Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D016023:Integrins; D015335:Molecular Probes; D000090802:rab7 GTP-Binding Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020558:GTP Phosphohydrolases; D020691:rab GTP-Binding Proteins; D018631:ras Proteins; D013890:Thiourea