RT Journal Article
T1 A Potent Isoprenylcysteine Carboxylmethyltransferase (ICMT) Inhibitor Improves Survival in Ras-Driven Acute Myeloid Leukemia
A1 Marín Ramos, Nagore Isasbel
A1 Balabasquer Peña, Moisés
A1 Ortega Nogales, Francisco Jesús
A1 Torrecillas, Iván R.
A1 Gil Ordoñez, Ana
A1 Marcos Ramiro, Beatriz
A1 Aguilar Garrido, Pedro
A1 Cushman, Ian
A1 Romero, Antonio
A1 Medrano, Francisco J.
A1 Gajate Fraile, Consuelo
A1 Mollinedo García, Faustino
A1 Philips, Mark R.
A1 Campillo, Mercedes
A1 Gallardo Delgado, Miguel
A1 Martín Fontecha, Mar
A1 López Rodríguez, María Luz
A1 Ortega Gutiérrez, Silvia
AB 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.
PB American chemical Society (ACS)
SN 0022-2623
YR 2019
FD 2019-06-10
LK https://hdl.handle.net/20.500.14352/13701
UL https://hdl.handle.net/20.500.14352/13701
LA eng
NO Received: January 24, 2019Published: June 10, 2019
NO Ministerio de Economía y Competitividad de España (MINECO)
DS Docta Complutense
RD 9 may 2024