From On‐Target to Off‐Target Activity: Identification and Optimisation of Trypanosoma brucei GSK3 Inhibitors and Their Characterisation as Anti‐Trypanosoma brucei Drug Discovery Lead Molecules. Issue 7 (14th June 2013)

• Record Type: Journal Article
• Authors: Woodland, Andrew; Grimaldi, Raffaella; Luksch, Torsten; Cleghorn, Laura A. T.; Ojo, Kayode K.; Van Voorhis, Wesley C.; Brenk, Ruth; Frearson, Julie A.; Gilbert, Ian H.; Wyatt, Paul G.
• Is Part Of: ChemMedChem. Volume 8:Issue 7(2013:Jul.)
• Page Start: 1127
• Page End: 1137
• Publication Date: 2013-06-14
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201300072
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>Human African trypanosomiasis (HAT) is a life‐threatening disease with approximately 30 000–40 000 new cases each year. <italic>Trypanosoma brucei</italic> protein kinase GSK3 short (<italic>Tb</italic>GSK3) is required for parasite growth and survival. Herein we report a screen of a focused kinase library against <italic>T. brucei</italic> GSK3. From this we identified a series of several highly ligand‐efficient <italic>Tb</italic>GSK3 inhibitors. Following the hit validation process, we optimised a series of diaminothiazoles, identifying low‐nanomolar inhibitors of <italic>Tb</italic>GSK3 that are potent in vitro inhibitors of <italic>T. brucei</italic> proliferation. We show that the <italic>Tb</italic>GSK3 pharmacophore overlaps with that of one or more additional molecular targets.</p> </abstract>