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Human African Trypanosomiasis (HAT), also known as sleeping sickness, is a lethal disease caused by two vector-borne parasites:Trypanosoma brucei gambienseandTrypanosoma brucei rhodesiense. The limited number of antitrypanosomal therapies for treating these deadly parasites suffer from toxicity, poor efficacy, and unspecified targets; thus, more and better medicines are needed. We usedin silicomethods to predict features of the bioactive compound AZ960 that make it an ortholog-specific inhibitor for the extracellular-signal regulated kinase 8 ofT. brucei(TbERK8). Our homology models showed that the TbERK8 ATP binding pocket was smaller and more hydrophobic than that of human ERK8 (HsERK8). Molecular docking studies predicted six FDA-approved compounds that would be orthologue-specific inhibitors of HsERK8 or TbERK8. Experimental testing of these compounds identified prednisolone as an HsERK8-specific inhibitor. Sildenafil inhibited TbERK8, as predicted by our binding model. Its impact on TbERK8 activity supports our hypothesis that designing compounds that can exploit differences in the orthologs as buildable scaffolds and expand the repertoire of ortholog-specific antitrypanosomal agents.