title: 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.
abstract: Human African trypanosomiasis (HAT) is a life-threatening disease with approximately 30 000-40 000 new cases each year. Trypanosoma brucei protein kinase GSK3 short (TbGSK3) is required for parasite growth and survival. Herein we report a screen of a focused kinase library against T. brucei GSK3. From this we identified a series of several highly ligand-efficient TbGSK3 inhibitors. Following the hit validation process, we optimised a series of diaminothiazoles, identifying low-nanomolar inhibitors of TbGSK3 that are potent in vitro inhibitors of T. brucei proliferation. We show that the TbGSK3 pharmacophore overlaps with that of one or more additional molecular targets.
authors.affiliation: Drug Discovery Unit (DDU), Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, DD1 5EH, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Woodland
authors.forename: Raffaella
authors.initials: R
authors.lastname: Grimaldi
authors.forename: Torsten
authors.initials: T
authors.lastname: Luksch
authors.forename: Laura A T
authors.initials: LA
authors.lastname: Cleghorn
authors.forename: Kayode K
authors.initials: KK
authors.lastname: Ojo
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
authors.forename: Ruth
authors.initials: R
authors.lastname: Brenk
authors.forename: Julie A
authors.initials: JA
authors.lastname: Frearson
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
authors.forename: Paul G
authors.initials: PG
authors.lastname: Wyatt
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology*
chemical_list: D047428:Protein Kinase Inhibitors; D014344:Trypanocidal Agents; D038362:Glycogen Synthase Kinase 3