Investigation of substrate and inhibitor specificities of the human isoprenylcysteine carboxyl methyltransferase (hIcmt) for the development of putative anti-cancer agents

Genetic mutations of Ras proteins lead to tumor and cancer formation. Mutated Ras proteins are involved in approximately 20-30% of all human cancers and 90% of pancreatic cancers. However, in order for the mutated Ras proteins to function they must first undergo a three-step post-translational processing pathway. Preventing any of these three modifications has been shown to hinder the transforming ability of cancer cell lines. Therefore, the three proteins involved in this modification pathway have recently been realized as critical targets for cancer pharmacotherapy. The main focus of this dissertation work was on investigating substrate and inhibitor specificities of the ER integral membrane protein isoprenylcysteine carboxylmethyltransferase (Icmt), the third protein in this modification pathway, in order to develop potent small molecule Icmt inhibitors as anti-cancer agents. These biochemical analyses have afforded us with information on Icmt active site characterization and enabled us to develop subsequent libraries of small molecules with the necessary inhibitory properties required by Icmt. Each successive library gained greater efficacy in eliminating Icmt function, supporting our conclusions from observations of inhibitor and substrate requirements and the success of our rational design. Results from this research will strongly contribute to the biochemical and cancer biology fields, as well as the field of pharmaceuticals for rational drug design