Development of a Nucleotide Exchange Inhibitor That Impairs Ras Oncogenic Signaling

Nagore I. Marín-Ramos, Carmen Piñar, Henar Vázquez-Villa, Mar Martín-Fontecha, Ángel González, Ángeles Canales, Sergio Algar, Paloma P. Mayo, Jesús Jiménez-Barbero, Consuelo Gajate, Faustino Mollinedo, Leonardo Pardo, Silvia Ortega-Gutiérrez, Alma Viso, María L. López-Rodríguez

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

Abstract

© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 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.
Original languageEnglish
Pages (from-to)1676-1685
JournalChemistry - A European Journal
Volume23
Issue number7
DOIs
Publication statusPublished - 1 Jan 2017

Keywords

  • cancer
  • drug design
  • inhibitors
  • medicinal chemistry
  • proteins

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