title: Development of a Nucleotide Exchange Inhibitor That Impairs Ras Oncogenic Signaling.
abstract: Despite more than three decades of intense effort, no anti-Ras therapies have reached clinical application. Contributing to this failure has been an underestimation of Ras complexity and a dearth of structural information. In this regard, recent studies have revealed the highly dynamic character of the Ras surface and the existence of transient pockets suitable for small-molecule binding, opening up new possibilities for the development of Ras modulators. Herein, a novel Ras inhibitor (compound 12) is described that selectively impairs mutated Ras activity in a reversible manner without significantly affecting wild-type Ras, reduces the Ras-guanosine triphosphate (GTP) levels, inhibits the activation of the mitogen-activated protein kinase (MAPK) pathway, and exhibits remarkable cytotoxic activity in Ras-driven cellular models. The use of molecular dynamics simulations and NMR spectroscopy experiments has enabled the molecular bases responsible for the interactions between compound 12 and Ras protein to be explored. The new Ras inhibitor binds partially to the GTP-binding region and extends into the adjacent hydrophobic pocket delimited by switch II. Hence, Ras inhibitor 12 could represent a new compound for the development of more efficacious drugs to target Ras-driven cancers; a currently unmet clinical need.
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain.|CEI Campus Moncloa, UCM-UPM and CSIC, 28040, Madrid, Spain.
authors.forename: Nagore I
authors.identifier: http://orcid.org/0000-0003-4712-0934
authors.initials: NI
authors.lastname: Marín-Ramos
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Piñar
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain.
authors.forename: Henar
authors.identifier: http://orcid.org/0000-0001-7911-3160
authors.initials: H
authors.lastname: Vázquez-Villa
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain.
authors.forename: Mar
authors.identifier: http://orcid.org/0000-0002-4848-0109
authors.initials: M
authors.lastname: Martín-Fontecha
authors.affiliation: Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain.
authors.forename: Ángel
authors.identifier: http://orcid.org/0000-0002-2284-8307
authors.initials: Á
authors.lastname: González
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain.
authors.forename: Ángeles
authors.identifier: http://orcid.org/0000-0003-0542-3080
authors.initials: Á
authors.lastname: Canales
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Algar
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain.
authors.forename: Paloma P
authors.initials: PP
authors.lastname: Mayo
authors.affiliation: CIC bioGUNE, Parque Tecnológico de Bizkaia, Edif. 801A, 48160, Derio, Spain.|Ikerbasque, Basque Foundation for Science, 48103, Bilbao, Spain.
authors.forename: Jesús
authors.identifier: http://orcid.org/0000-0001-5421-8513
authors.initials: J
authors.lastname: Jiménez-Barbero
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas, CSIC, 28040, Madrid, Spain.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Gajate
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas, CSIC, 28040, Madrid, Spain.
authors.forename: Faustino
authors.identifier: http://orcid.org/0000-0002-4939-2434
authors.initials: F
authors.lastname: Mollinedo
authors.affiliation: Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain.
authors.forename: Leonardo
authors.identifier: http://orcid.org/0000-0003-1778-7420
authors.initials: L
authors.lastname: Pardo
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain.
authors.forename: Silvia
authors.identifier: http://orcid.org/0000-0002-0257-6754
authors.initials: S
authors.lastname: Ortega-Gutiérrez
authors.affiliation: Instituto de Química Orgánica General, IQOG-CSIC, Juan de la Cierva, 3, 28006, Madrid, Spain.
authors.forename: Alma
authors.identifier: http://orcid.org/0000-0003-2622-4777
authors.initials: A
authors.lastname: Viso
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040, Madrid, Spain.
authors.forename: María L
authors.identifier: http://orcid.org/0000-0001-8607-1085
authors.initials: ML
authors.lastname: López-Rodríguez
keywords: cancer; drug design; inhibitors; medicinal chemistry; proteins