Cysmethynil

Post-translational protein prenylation is a 3-step process that occurs at the C-terminus of a number of proteins involved in cell growth control and oncogenesis. Isoprenylcysteine carboxyl methyltransferase (Icmt) catalyzes the methylation of C-terminal prenylcysteine residues, the last step in this process. Cysmethynil is an indole-based, time-dependent inhibitor of Icmt (IC₅₀ = <200 nM).¹ It acts as a competitive inhibitor with respect to the isoprenylated cysteine substrate and a noncompetitive inhibitor with respect to S-adenosylmethionine (K_i = 0.14 µM for the final complex).² It does not inhibit other enzymes in the prenylation pathway (farensyltransferase, geranylgeranyltransferase type I, and Rce1) at concentrations up to 50 µM, or related methyltransferases.¹ Treatment of cancer cells results in a dose-dependent decrease in Ras carboxylmethylation, mislocalization of Ras, and impaired signaling through Ras pathways.¹ Treatment of PC3 prostate cancer cells with 25 µM cysmethynil resulted in decreased mTOR signaling, accumulation of cells in the G₁ phase, and autophagy-mediated cell death.³

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1. Winter-Vann, A.M., Baron, R.A., Wong, W., et al. A small-molecule inhibitor of isoprenylcysteine carboxyl methyltransferase with antitumor activity in cancer cells. Proc. Natl. Acad. Sci. USA 102(12), 4336-4341 (2005).

2. Baron, R.A., Peterson, Y.K., Otto, J.C., et al. Time-dependent inhibition of isoprenylcysteine carboxyl methyltransferase by indole-based small molecules. Biochemistry 46(2), 554-560 (2007).

3. Wang, M., Tan, W., Zhou, J., et al. A small molecule inhibitor of isoprenylcysteine carboxymethyltransferase induces autophagic cell death in PC3 prostate cancer cells. The Journal of Biological Chemisty 283(27), 18678-18684 (2008).