Marín Ramos, Nagore IsasbelBalabasquer Peña, MoisésOrtega Nogales, Francisco JesúsTorrecillas, Iván R.Gil Ordóñez, AnaMarcos Ramiro, BeatrizAguilar Garrido, PedroCushman, IanRomero, AntonioMedrano, Francisco J.Gajate Fraile, ConsueloMollinedo García, FaustinoPhilips, Mark R.Campillo, MercedesGallardo Delgado, MiguelMartín-Fontecha Corrales, María Del MarLópez Rodríguez, María LuzOrtega Gutiérrez, Silvia2023-06-172023-06-172019-06-100022-262310.1021/acs.jmedchem.9b00145https://hdl.handle.net/20.500.14352/13701Received: January 24, 2019 Published: June 10, 2019Blockade 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.engjournal articlehttps://doi.org/10.1021/acs.jmedchem.9b00145restricted access577.15547616.155.392Small-molecule inhibitorsOncogenic k-rasCarboxyl methyltransferaseAntitumor-activityCell-death MechanismApoptosisFarnesylFarnesyltrastransferasePrenylationPrenylated proteinsICMTMyeloid leukemiaBioquímica (Química)Química orgánica (Química)Oncología2306 Química Orgánica3201.01 Oncología