2. Academic Validation
  3. Discovery and antiparasitic activity of AZ960 as a Trypanosoma brucei ERK8 inhibitor

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

  • Bioorg Med Chem. 2016 Oct 1;24(19):4647-4651. doi: 10.1016/j.bmc.2016.07.069.
Ana L Valenciano 1,  Aaron C Ramsey 1,  Webster L Santos 2,  Zachary B Mackey 3
Affiliations

Affiliations

  • 1 Department of Biochemistry and Fralin Life Science Institute, Vector-Borne Disease Division, Virginia Tech, Blacksburg, VA 24061, USA.
  • 2 Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA; Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA.
  • 3 Department of Biochemistry and Fralin Life Science Institute, Vector-Borne Disease Division, Virginia Tech, Blacksburg, VA 24061, USA; Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA. Electronic address: [email protected].
PMID: 27519462 DOI: 10.1016/j.bmc.2016.07.069
Abstract

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.

Keywords

AZ960; Extracellular-signal regulated kinase (ERK); High-throughput screening; Mitogen-activated protein kinase (MAPK); Trypanosoma brucei.

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