1. From On-Target to Off-Target Activity: Identification and Optimisation ofTrypanosoma bruceiGSK3 Inhibitors and Their Characterisation as Anti-Trypanosoma bruceiDrug Discovery Lead Molecules
- Author
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Andrew Woodland, Torsten Luksch, Julie A. Frearson, Kayode K. Ojo, Paul G. Wyatt, Ian H. Gilbert, Ruth Brenk, Laura A. T. Cleghorn, Wesley C. Van Voorhis, and Raffaella Grimaldi
- Subjects
Models, Molecular ,Trypanosoma brucei brucei ,Biology ,Trypanosoma brucei ,Biochemistry ,GSK3 ,Cell Line ,Glycogen Synthase Kinase 3 ,Structure-Activity Relationship ,03 medical and health sciences ,Parasitic Sensitivity Tests ,medicinal chemistry ,parasitic diseases ,Drug Discovery ,medicine ,Humans ,Structure–activity relationship ,African trypanosomiasis ,General Pharmacology, Toxicology and Pharmaceutics ,Protein kinase A ,Protein Kinase Inhibitors ,Cell Proliferation ,030304 developmental biology ,Pharmacology ,protein kinases ,0303 health sciences ,Dose-Response Relationship, Drug ,Molecular Structure ,030306 microbiology ,Drug discovery ,Kinase ,Organic Chemistry ,Full Papers ,medicine.disease ,biology.organism_classification ,Trypanocidal Agents ,In vitro ,3. Good health ,Molecular Medicine ,Pharmacophore ,antiprotozoal agents - 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.
- Published
- 2013
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