Discovery and antiparasitic activity of AZ960 as a Trypanosoma brucei ERK8 inhibitor

Publication date: 1 October 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
Author(s): Ana L. Valenciano, Aaron C. Ramsey, Webster L. Santos, Zachary B. Mackey
Human African trypanosomiasis (HAT) is a lethal, vector-borne disease caused by the parasite Trypanosoma brucei. Therapeutic strategies for this neglected tropical disease suffer from disadvantages such as toxicity, high cost, and emerging resistance. Therefore, new drugs with novel modes of action are needed. We screened cultured T. brucei against a focused kinase inhibitor library to identify promising bioactive compounds. Among the ten hits identified from the phenotypic screen, AZ960 emerged as the most promising compound with potent antiparasitic activity (IC50=120nM) and was shown to be a selective inhibitor of an essential gene product, T. brucei extracellular signal-regulated kinase 8 (TbERK8). We report that AZ960 has a Ki of 1.25μM for TbERK8 and demonstrate its utility in establishing TbERK8 as a potentially druggable target in T. brucei.

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