AFC analogs as ICMT inhibitors

Brian S Henriksen, Purdue University


Isoprenyl cysteine methyltransferase (Icmt) is a membrane bound enzyme that catalyzes the methyl esterification of Ras. This methyl esterification is important in the proper localization of Ras to the plasma membrane, and thus its biological activity. Ras is implicated in ∼30% of human cancer, and in 90% of pancreatic cancer. Therefore small molecules that mislocalize Ras are an attractive therapeutic approach to cancers of this kind. We have performed the first structure activity relationship studies on the isoprenoid chain of N-Acetyl famesyl cysteine (AFC), the minimal synthetic substrate for Icmt. This work led to the synthesis of a small library of prenyl modified analogs and the discovery of the lead inhibitor N-Acetyl (3-isobutenylfarnesyl) Cysteme (Ki = 13.1 μM). To further elaborate the SAR of AFC and develop more potent Icmt inhibitors, modifications to the cysteine amine are of significant interest. Development of a novel solid phase methodology for the synthesis of acyl variants of AFC has been accomplished. The lead amine and isoprenoid modifications can be utilized to design the next generation of Icmt inhibitors. Additionally, the structural content of the prenyl and amine binding regions will be investigated with novel photoaffinity labels, and the binding requirement around the allylic thioether of AFC has been elucidated with an "all-carbon" bioisostere, which has been synthesized as part of this project. Finally, preliminary work has been completed to utilize protein farnesyltransferase (FTase) as a model system for the evaluation of analogs bearing prenyl moieties in silico through the use of computational docking, pharmacophore construction and quantitative structure activity relationship studies.




Gibbs, Purdue University.

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