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

TY - JOUR

T1 - From on-target to off-target activity

T2 - identification and optimisation of Trypanosoma brucei GSK3 inhibitors and their characterisation as anti-Trypanosoma brucei drug discovery lead molecules

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

N1 - © 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.

PY - 2013/7

Y1 - 2013/7

N2 - 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.

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.

U2 - 10.1002/cmdc.201300072

DO - 10.1002/cmdc.201300072

M3 - Article

C2 - 23776181

SN - 1860-7179

VL - 8

SP - 1127

EP - 1137

JO - ChemMedChem

JF - ChemMedChem

IS - 7

ER -