Development of a Nucleotide Exchange Inhibitor That Impairs Ras Oncogenic Signaling



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Marín Ramos, Nagore Isasbel and Piñar Pinedo, María del Carmen and Vázquez Villa, Henar and Martín Fontecha, María del Mar and Gonzalez Wong, Ángel and Canales Mayordomo, Ángeles and Algar Lizana, Sergio and Mayo Mariscal de Gante, Paloma P. and Jiménez-Barbero, Jesús and Gajate Fraile, Consuelo and Mollinedo García, Faustino and Pardo Carrasco, Leonardo and Ortega Gutiérrez, Silvia and Viso Beronda, Alma and López Rodríguez, María Luz (2017) Development of a Nucleotide Exchange Inhibitor That Impairs Ras Oncogenic Signaling. Chemistry: a european journal, 23 (7). pp. 1676-1685. ISSN 0947-6539

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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.

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Manuscript Received: 20 October 2016; Accepted manuscript online: 25 November 2016; Version of record online: 27 December 2016; Issue online: 1 February 2017

Uncontrolled Keywords:Cancer; Drug design; Inhibitors; Medicinal chemistry; Proteins
Subjects:Medical sciences > Medicine > Biochemistry
Medical sciences > Medicine > Oncology
ID Code:45837
Deposited On:21 Dec 2017 11:15
Last Modified:22 Dec 2017 08:27

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