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Ref Type Journal Article
PMID (31181882)
Authors Marín-Ramos NI, Balabasquer M, Ortega-Nogales FJ, Torrecillas IR, Gil-Ordóñez A, Marcos-Ramiro B, Aguilar-Garrido P, Cushman I, Romero A, Medrano FJ, Gajate C, Mollinedo F, Philips MR, Campillo M, Gallardo M, Martín-Fontecha M, López-Rodríguez ML, Ortega-Gutiérrez S
Title A Potent Isoprenylcysteine Carboxylmethyltransferase (ICMT) Inhibitor Improves Survival in Ras-Driven Acute Myeloid Leukemia.
Journal Journal of medicinal chemistry
Vol 62
Issue 13
Date 2019 07 11
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
UCM-1336 UCM-1336 2 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
UCM-1336 UCM1336|UCM 1336 UCM-1336 is an inhibitor of isoprenylcysteine carboxylmethyltransferase (ICMT), which may result in mislocalization of Ras, decreased Ras activity, and induction of cell death (PMID: 31181882).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NRAS Q61K melanoma predicted - sensitive UCM-1336 Preclinical - Cell culture Actionable In a preclinical study, UCM-1336 treatment inhibited growth of melanoma cells harboring NRAS Q61K in culture (PMID: 31181882). 31181882
NRAS Q61K acute myeloid leukemia predicted - sensitive UCM-1336 Preclinical - Cell line xenograft Actionable In a preclinical study, UCM-1336 treatment inhibited growth of acute myeloid leukemia cells harboring NRAS Q61K in culture, and reduced bone marrow tumor burden and significantly prolonged survival (HR=6.211; p=0.0274) in cell line xenograft models (PMID: 31181882). 31181882