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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.

SUBMITTER: Woodland A 

PROVIDER: S-EPMC3728731 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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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.

Woodland Andrew A   Grimaldi Raffaella R   Luksch Torsten T   Cleghorn Laura A T LA   Ojo Kayode K KK   Van Voorhis Wesley C WC   Brenk Ruth R   Frearson Julie A JA   Gilbert Ian H IH   Wyatt Paul G PG  

ChemMedChem 20130614 7

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 inhibito  ...[more]

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