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A potent isoprenylcysteine carboxylmethyltransferase (ICMT) inhibitor improves survival in ras-driven acute myeloid leukemia

AuthorsMarín-Ramos, Nagore I.; Balabasquer, Moisés; Ortega-Nogales, Francisco J.; Torrecillas, I. R.; Gil-Ordóñez, Ana; Marcos-Ramiro, Beatriz; Aguilar-Garrido, Pedro; Cushman, Ian; Romero, Antonio CSIC ORCID ; Medrano, Francisco Javier CSIC ORCID ; Gajate, Consuelo CSIC ORCID ; Mollinedo, Faustino CSIC ORCID ; Philips, Mark R.; Campillo, M.; Gallardo, Miguel; Martín-Fontecha, Mar; López-Rodríguez, María L.; Ortega-Gutiérrez, S.
KeywordsSmall-molecule inhibitors
Oncogenic k-ras
Carboxyl methyltransferase
Issue Date11-Jul-2019
PublisherAmerican Chemical Society
CitationJ Med Chem 62(13):6035-6046 (2019)
AbstractBlockade 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.
Description12 p.-9 fig.-6 tab.-1 graph. abst.
Publisher version (URL)https://doi.org/10.1021/acs.jmedchem.9b00145
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