Mutant K-Ras proteins are key drivers in ~90% of human pancreatic carcinomas.  K-Ras is modified post-translationally via prenylation, proteolysis, and a-carboxyl methylation.  Both prenylation and methylation are necessary for the proper localization and biological function of K-Ras.  Thus, there is great interest in blocking the methylation of K-Ras by human isoprenylcysteine carboxyl methyltransferase (hIcmt) as a route to block its activity in tumor cells.  We have developed a readily-synthesized class of nanomolar hIcmt inhibitors based on the substrate N-acetyl-farnesyl cysteine (AFC).  Elaboration of the structure-function relationships around these compounds led to our current lead compound, sTAB-F3-Diol, which has a Ki of approximately 50 nM against hIcmt.   sTAB-F3-Diol also blocked cellular Ras activation, interfered with Ras signaling through Erk, and exhibited nanomolar to low micromolar GI50 values versus pancreatic tumor cells in vitro.  We are currently further optimizing the biochemical activity and drug-like characteristics of this potent and promising agent.

Inhibitors of Ras carboxyl methyltransferase as potential treatments for pancreatic cancer

245th National Meeting (2013)

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