Isoprenylcysteine carboxylmethyltransferase (ICMT) (ICMT)

Isoprenylcysteine carboxylmethyltransferase (ICMT) is an integral membrane enzyme located in the endoplasmic reticulum that catalyzes the final step of the post-translational processing of CaaX-motif proteins, including RAS GTPases and nuclear lamins. By methylating the carboxyl group of the prenylated cysteine residue, ICMT increases the hydrophobicity of the protein's C-terminus, which is essential for its proper localization to the plasma membrane and subsequent biological activity. Because many of its substrates, such as RAS and Rho family proteins, are key drivers of oncogenesis, ICMT has emerged as a significant therapeutic target for various cancers, including pancreatic, lung, and colon cancers. Inhibition of ICMT leads to the mislocalization of these proteins, disrupting critical signaling pathways like MAPK and PI3K/Akt, and has been shown to induce cell cycle arrest, autophagy, and apoptosis in cancer cells. Beyond oncology, ICMT inhibition is being explored for the treatment of Hutchinson-Gilford Progeria Syndrome, as it prevents the toxic accumulation of progerin. Experimental inhibitors like cysmethynil and its derivatives have demonstrated efficacy in preclinical models, although challenges such as solubility and potential broad-spectrum effects remain. Recent studies also suggest that ICMT plays a role in DNA damage repair and mitochondrial respiration, further expanding its potential as a multi-faceted therapeutic target.

Other names

Protein-S-isoprenylcysteine O-methyltransferasePrenylcysteine carboxylmethyltransferasePrenylated protein carboxyl methyltransferasePCMTHSTE14

Inhibition of the carboxylmethylation of prenylated proteins (CaaX proteins), which prevents their proper membrane association and disrupts downstream oncogenic signaling pathways such as MAPK and PI3K/Akt.