Investigating the Structural Criteria for Icmt Inhibition: Development of AFC and FTA-triazole based Icmt Inhibitors
Abstract
Mutant K-Ras is a key oncogene in pancreatic cancer and several other neoplasias. For Ras proteins to be constitutively active, C-terminal carboxylmethylation by isoprenylcysteine carboxyl methyltransferase (Icmt) is crucial. Icmt inhibition leads to Ras mislocalization, inhibition of oncogenic K-Ras transformation, and signaling impairment of the Ras/Raf/Mek/Erk pathway. In order to develop Icmt inhibitors, we have modified the amide and prenyl moiety of N-Acetyl-S-Farnesyl Cysteine (AFC). While amide modification contributes to inhibitory potency, the prenyl modifications play a key role in Icmt activity. More recent and productive studies have focused on the replacement of biphenyl moiety of our lead compound sTAB (short triazole and biphenyl farnesyl thiopropionic acid). The synthesis and evaluation of a set of biphenyl-modified sTAB analogs confirmed that this moiety is a significant pharmacophore required for enzyme inhibition, and resulted in the discovery of low nanomolar inhibitors. We then investigated both the replacement of the hydrolytically labile ester and the central 1,2,3-triazole linker. Both the ester and triazole moieties have been successfully replaced, leading to the discovery of diverse sTAB analogs exhibiting low nanomolar Icmt inhibition, including compounds with promising effects on pancreatic tumor cells.
Degree
Ph.D.
Advisors
Gibbs, Purdue University.
Subject Area
Organic chemistry|Pharmacy sciences
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