Synthesis of isoprenoids and isoprenoid mimetics: Development of novel nanomolar Icmt inhibitors

The post-translation modification of the Ras proteins is critical to their biological activity. Targeting the enzymes that facilitate these transformations represents a potential therapeutic target for cancer therapies. Inhibiting the last step, catalyzed by Icmt, is an attractive strategy because there is no other known methyltransferase capable of facilitating this reaction and is a focus of the research of our laboratory. Prenyl-modified AFC analogs have been shown to inhibit Icmt, and a library of 12 compounds further developed requirements for enzyme inhibition. Notably, the introduction of aryl motifs must be accompanied by flexibility in the prenyl chain. Also investigated was the modification of the cysteine backbone with known AMFC modifications. This resulted in modest inhibitors of Icmt. More importantly, this substitution fueled the removal of the amide region to focus on the prenyl group and cysteine backbone by synthesizing a library of FTP/FTA analogs. Lastly a library of FTP-triazole compounds of FTP and FTP resulted potent inhibitors of Icmt. Important structural motifs identified were flexibility about the second isoprene triazole and a 4-biphenyl motif are critical for potent Icmt inhibition. This approach led to the discovery of STAB, the most potent Icmt inhibitor to date with an IC50 of 200 nM