From kinetoplastids to cancer: A magical myristate tour

Abstract

Myristic acid (14:0) is a relatively minor fatty acid in terms of abundance yet, in certain biological settings, it has a major impact. Although normally synthesized via the classical fatty acid biosynthesis pathway, in specific cases where larger quantities of myristate are required, animals express distinct thioesterase enzymes that hydrolyze the acyl-S-fatty acid synthase thioester bond prior to further chain elongation. In the parasitic kinetoplastid, Trypanosoma brucei, myristate is required for biosynthesis of dimyristoyl-glycosylphosphatidylinositol membrane anchors, to which variable surface glycoproteins are attached. This extracellular coat protein is changed periodically, allowing the parasite to evade host adaptive immunity. In protein N-myristoylation, this acyl chain is attached to N-terminal glycine residues via an amide bond. A search for inhibitors of N-myristoyltransferase (NMT) activity led to discovery of pyrazole sulfonamide compounds with potent T. brucei NMT inhibitory activity. While clinical development of these inhibitors for parasite-induced disease has not been realized, the observation that pyrazole sulfonamides possess anticancer activity led to drug development studies. Findings obtained with a specific pyrazole sulfonamide compound, branded as zelenirstat, have yielded promising results in cell culture studies, animal models and human clinical trials. This review describes research undertaken to validate zelenirstat as a cancer therapy option.