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

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Marín Ramos, Nagore Isasbel and Balabasquer Peña, Moisés and Ortega Nogales, Francisco Jesús and Torrecillas, Iván R. and Gil Ordoñez, Ana and Marcos Ramiro, Beatriz and Aguilar Garrido, Pedro and Cushman, Ian and Romero, Antonio and Medrano, Francisco J. and Gajate Fraile, Consuelo and Mollinedo García, Faustino and Philips, Mark R. and Campillo, Mercedes and Gallardo Delgado, Miguel and Martín Fontecha, Mar and López Rodríguez, María Luz and Ortega Gutiérrez, Silvia (2019) A Potent Isoprenylcysteine Carboxylmethyltransferase (ICMT) Inhibitor Improves Survival in Ras-Driven Acute Myeloid Leukemia. Journal of Medicinal Chemistry, 62 (13). pp. 6035-6046. ISSN 0022-2623

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Official URL: https://doi.org/10.1021/acs.jmedchem.9b00145



Abstract

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.


Item Type:Article
Additional Information:

Received: January 24, 2019
Published: June 10, 2019

Uncontrolled Keywords:Small-molecule inhibitors, Oncogenic k-ras; Carboxyl methyltransferase; Antitumor-activity; Cell-death Mechanism; Apoptosis; Farnesyl; Farnesyltrastransferase; Prenylation; Prenylated proteins; ICMT; Myeloid leukemia
Subjects:Sciences > Chemistry > Biochemistry
Sciences > Chemistry > Chemistry, Organic
Medical sciences > Medicine > Oncology
ID Code:57428
Deposited On:14 Nov 2019 08:23
Last Modified:14 Nov 2019 08:30

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