Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Journal of medicinal chemistry	62	13	2019 07 11	6035-6046	J Med Chem

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	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
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