title: Discovery and antiparasitic activity of AZ960 as a Trypanosoma brucei ERK8 inhibitor.
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.
authors: Department of Biochemistry and Fralin Life Science Institute, Vector-Borne Disease Division, Virginia Tech, Blacksburg, VA 24061, USA.
authors: Ana L
authors: AL
authors: Valenciano
authors: Department of Biochemistry and Fralin Life Science Institute, Vector-Borne Disease Division, Virginia Tech, Blacksburg, VA 24061, USA.
authors: Aaron C
authors: AC
authors: Ramsey
authors: Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA; Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA.
authors: Webster L
authors: WL
authors: Santos
authors: 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: mackeyzb@vt.edu.
authors: Zachary B
authors: ZB
authors: Mackey
mesh_terms: D000631:Aminopyridines / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D014353:Trypanosomiasis, African / Q000188:drug therapy*
chemical_list: C534391:5-fluoro-2-(1-(4-fluorophenyl)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)nicotinonitrile; D000631:Aminopyridines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011994:Recombinant Proteins; D014344:Trypanocidal Agents; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: AZ960; Extracellular-signal regulated kinase (ERK); High-throughput screening; Mitogen-activated protein kinase (MAPK); Trypanosoma brucei