Cysmethynil, a Specific Small-Molecule Inhibitor of Isoprenylcysteine Carboxylmethyl Transferase (Icmt)

Abstract

Since the discovery that Ras oncoproteins undergo processing through the CAAX prenylation pathway and that the modification is important for their function, this process had been under the spotlight in the hope to develop effective inhibitors for cancer therapy. It is increasingly recognized that C-terminal methylation, the last step of this modification process catalyzed by isoprenylcysteine carboxylmethyl transferase (Icmt), impacts the functions of both farnesylated as well as geranylgeranylated CAAX proteins. With the increasing understanding that numerous CAAX proteins, both farnesylated and geranylgeranylated, can contribute to pathological conditions such as cancer and inflammation, there is substantial interest in development of effective and specific inhibitors of Icmt as novel therapeutics. Cysmethynil is specific small molecular inhibitor of Icmt that is not a substrate analog; the compound was discovered through screening of a diverse chemical library for compounds that directly inhibit Icmt in vitro. Cysmethynil treatment inhibits cancer cell proliferation, increases cellular autophagy and induces cell death in an Icmt-dependent manner. Additionally, cysmethynil treatment of metastatic breast cancer cells impairs their migration and invasion via selective impact on Rho and Rac proteins. Cysmethynil has also demonstrated efficacy in vivo in xenograft tumor models. Identification of the downstream effectors of cysmethynil treatment, that is, the specific CAAX proteins whose function is altered by the absence of C-terminal methylation, should be informative both in understanding the mechanistic importance of this modification as well as in the design of novel therapeutics. © 2011 Elsevier Inc.