RT Journal Article
T1 Development of a Nucleotide Exchange Inhibitor That Impairs Ras Oncogenic Signaling
A1 Marín Ramos, Nagore Isasbel
A1 Piñar Pinedo, María del Carmen
A1 Vázquez Villa, Henar
A1 Martín Fontecha, María del Mar
A1 Gonzalez Wong, Ángel
A1 Canales Mayordomo, Ángeles
A1 Algar Lizana, Sergio
A1 Mayo Mariscal de Gante, Paloma P.
A1 Jiménez-Barbero, Jesús
A1 Gajate Fraile, Consuelo
A1 Mollinedo García, Faustino
A1 Pardo Carrasco, Leonardo
A1 Ortega Gutiérrez, Silvia
A1 Viso Beronda, Alma
A1 López Rodríguez, María Luz
AB 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.
PB Wiley
SN 0947-6539
YR 2017
FD 2017-01-31
LK https://hdl.handle.net/20.500.14352/18289
UL https://hdl.handle.net/20.500.14352/18289
LA eng
NO Manuscript Received: 20 October 2016; Accepted manuscript online: 25 November 2016; Version of record online: 27 December 2016; Issue online: 1 February 2017
NO Ministerio de Economía y Competitividad (MINECO)
NO Comunidad de Madrid
DS Docta Complutense
RD 6 may 2024