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

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.