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

Andrew Woodland, Raffaella Grimaldi, Torsten Luksch, Laura A T Cleghorn, Kayode K Ojo, Wesley C. Van Voorhis, Ruth Brenk, Julie A. Frearson, Ian H Gilbert (Lead / Corresponding author), Paul G Wyatt (Lead / Corresponding author)

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    17 Citations (Scopus)

    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.
    Original languageEnglish
    Pages (from-to)1127-1137
    Number of pages11
    JournalChemMedChem
    Volume8
    Issue number7
    DOIs
    Publication statusPublished - Jul 2013

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    Trypanosoma brucei brucei
    Drug Discovery
    Protein Kinases
    Phosphotransferases
    Ligands
    Molecules
    African Trypanosomiasis
    Parasites
    Survival
    Growth

    Cite this

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    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.",
    author = "Andrew Woodland and Raffaella Grimaldi and Torsten Luksch and Cleghorn, {Laura A T} and Ojo, {Kayode K} and {Van Voorhis}, {Wesley C.} and Ruth Brenk and Frearson, {Julie A.} and Gilbert, {Ian H} and Wyatt, {Paul G}",
    note = "{\circledC} 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.",
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    AU - Woodland, Andrew

    AU - Grimaldi, Raffaella

    AU - Luksch, Torsten

    AU - Cleghorn, Laura A T

    AU - Ojo, Kayode K

    AU - Van Voorhis, Wesley C.

    AU - Brenk, Ruth

    AU - Frearson, Julie A.

    AU - Gilbert, Ian H

    AU - Wyatt, Paul G

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    AB - 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.

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