2. Academic Validation
  3. A Potent Isoprenylcysteine Carboxylmethyltransferase (ICMT) Inhibitor Improves Survival in Ras-Driven Acute Myeloid Leukemia

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

  • J Med Chem. 2019 Jul 11;62(13):6035-6046. doi: 10.1021/acs.jmedchem.9b00145.
Nagore I Marín-Ramos 1 2,  Moisés Balabasquer 1,  Francisco J Ortega-Nogales 1,  Iván R Torrecillas 3,  Ana Gil-Ordóñez 1,  Beatriz Marcos-Ramiro 1,  Pedro Aguilar-Garrido 4,  Ian Cushman 5,  Antonio Romero 6,  Francisco J Medrano 6,  Consuelo Gajate 6,  Faustino Mollinedo 6,  Mark R Philips 7,  Mercedes Campillo 3,  Miguel Gallardo 4,  Mar Martín-Fontecha 1,  María L López-Rodríguez 1,  Silvia Ortega-Gutiérrez 1
Affiliations

Affiliations

  • 1 Departamento de Química Orgánica I, Facultad de Ciencias Químicas , Universidad Complutense de Madrid , E-28040 Madrid , Spain.
  • 2 CEI Campus Moncloa , UCM-UPM and CSIC , E-28040 Madrid , Spain.
  • 3 Laboratori de Medicina Computacional, Unitat de Bioestadística, Facultat de Medicina , Universitat Autònoma de Barcelona , E-08193 Bellaterra , Barcelona , Spain.
  • 4 H12O-CNIO Haematological Malignancies Clinical Research Unit , Centro Nacional de Investigaciones Oncológicas (CNIO) , E-28029 Madrid , Spain.
  • 5 Department of Pharmacology and Cancer Biology , Duke University Medical Center , Durham , North Carolina 27710 , United States.
  • 6 Centro de Investigaciones Biológicas, CSIC , E-28040 Madrid , Spain.
  • 7 Perlmutter Cancer Center , New York University School of Medicine , New York , New York 10016 , United States.
PMID: 31181882 DOI: 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.

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