Poster Presentation 25th Lorne Cancer Conference 2013

Small molecule inhibitors of ICMT as potential cancer therapeutics (#254)

Aaron M Lock 1 2 , Grant D Stuchbury 1 2 , Tayner Rodriguez 1 2 , Graeme Stevenson 3 , Vicky M Avery 1 2
  1. Discovery Biology, Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane, QLD, Australia
  2. CTx Biology Group, Cancer Therapeutics CRC, Brisbane, QLD, Australia
  3. CTx Medicinal Chemistry Group, Cancer Therapeutics CRC, Brisbane, QLD, Australia

Isoprenyl cysteine carboxymethyl transferase (ICMT) performs the final step in the post-translational modification of proteins bearing a C-terminal –Caax motif. Following isoprenylation of the cysteine residue and cleavage of the three terminal peptides, ICMT utilizes S-adenosyl-methionine as a substrate to methylate the C-terminal cysteine. This process is necessary for appropriate membrane localisation and protein stabilisation and there are >100 proteins that contain the C-term-Caax motif including the Ras, Rho and Rab families. As many of these proteins are involved in regulating various pathways critical in tumourigenesis ICMT presents itself as an possible anti-cancer target.

An in vitro Scintillation Promixity Assay (SPA)-based ICMT bioassay was used to perform high-throughput screening of chemical libraries to identify inhibitors with potential anti-cancer activity. A selection of actives was subjected to a lead identification programme that included the high content imaging of ICMT client proteins as a means of confirming small molecule inhibitors able to inhibit the protein methylation step. The outcomes from these studies will be presented.