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Extended-spectrum antiprotozoal bumped kinase inhibitors: A review

Van Voorhis, Wesley C., Doggett, J. Stone, Parsons, Marilyn, Hulverson, Matthew A., Choi, Ryan, Arnold, Samuel L.M., Riggs, Michael W., Hemphill, Andrew, Howe, Daniel K., Mealey, Robert H., Lau, Audrey O.T., Merritt, Ethan A., Maly, Dustin J., Fan, Erkang, Ojo, Kayode K.
Experimental parasitology 2017
Miozoa, animals, models, parasites, parasitoses, pharmacokinetics, protein kinases, protein phosphorylation, therapeutics
Many life-cycle processes in parasites are regulated by protein phosphorylation. Hence, disruption of essential protein kinase function has been explored for therapy of parasitic diseases. However, the difficulty of inhibiting parasite protein kinases to the exclusion of host orthologues poses a practical challenge. A possible path around this difficulty is the use of bumped kinase inhibitors for targeting calcium-dependent protein kinases that contain atypically small gatekeeper residues and are crucial for pathogenic apicomplexan parasites' survival and proliferation. In this article, we review efficacy against the kinase target, parasite growth in vitro, and in animal infection models, as well as the relevant pharmacokinetic and safety parameters of bumped kinase inhibitors.