Functionalized indoleamines as potent, drug-like inhibitors of isoprenylcysteine carboxyl methyltransferase (Icmt)

The Enzyme isoprenylcysteine carboxyl methyltransferase (ICMT) plays an important role in the post-translational modification of proteins involved in the regulation of cell growth and oncogenesis. The biological consequences of ICMT inhibition strongly implicate the Enzyme as a potential therapeutic target for Cancer and provide a compelling rationale for developing specific ICMT inhibitors as anti-cancer agents. We report here the systematic modification of the known ICMT Inhibitor cysmethynil to give an analog 15 with greatly improved solubility and PAMPA permeability which was achieved with concurrent gains in ICMT inhibitory and cell-based antiproliferative activities. The modifications involved replacing the amide side chain of cysmethynil with a tertiary amine, and introducing an aminopyrimidine ring in place of m-tolyl. The presence of the weakly basic and polar aminopyrimidine ring contributed significantly to the potency and drug-like profile of the final compound.