A Potent Isoprenylcysteine Carboxylmethyltransferase (ICMT) Inhibitor Improves Survival in Ras-Driven Acute Myeloid Leukemia

Nagore I. Marín-Ramos, Moisés Balabasquer, Francisco J. Ortega-Nogales, Iván R. Torrecillas, Ana Gil-Ordóñez, Beatriz Marcos-Ramiro, Pedro Aguilar-Garrido, Ian Cushman, Antonio Romero, Francisco J. Medrano, Consuelo Gajate, Faustino Mollinedo, Mark R. Philips, Mercedes Campillo, Miguel Gallardo, Mar Martín-Fontecha, María L. López-Rodríguez, Silvia Ortega-Gutiérrez

Research output: Contribution to journalArticleResearch

5 Citations (Scopus)

Abstract

© 2019 American Chemical Society. Blockade of Ras activity by inhibiting its post-translational methylation catalyzed by isoprenylcysteine carboxylmethyltransferase (ICMT) has been suggested as a promising antitumor strategy. However, the paucity of inhibitors has precluded the clinical validation of this approach. In this work we report a potent ICMT inhibitor, compound 3 [UCM-1336, IC50 = 2 μM], which is selective against the other enzymes involved in the post-translational modifications of Ras. Compound 3 significantly impairs the membrane association of the four Ras isoforms, leading to a decrease of Ras activity and to inhibition of Ras downstream signaling pathways. In addition, it induces cell death in a variety of Ras-mutated tumor cell lines and increases survival in an in vivo model of acute myeloid leukemia. Because ICMT inhibition impairs the activity of the four Ras isoforms regardless of its activating mutation, compound 3 surmounts many of the common limitations of available Ras inhibitors described so far. In addition, these results validate ICMT as a valuable target for the treatment of Ras-driven tumors.
Original languageEnglish
Pages (from-to)6035-6046
JournalJournal of Medicinal Chemistry
Volume62
DOIs
Publication statusPublished - 10 Jun 2019

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