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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
Author(s) -
Woodland Andrew,
Grimaldi Raffaella,
Luksch Torsten,
Cleghorn Laura A. T.,
Ojo Kayode K.,
Van Voorhis Wesley C.,
Brenk Ruth,
Frearson Julie A.,
Gilbert Ian H.,
Wyatt Paul G.
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300072
Subject(s) - trypanosoma brucei , pharmacophore , drug discovery , african trypanosomiasis , biology , drug target , computational biology , drug development , drug , biochemistry , pharmacology , virology , trypanosomiasis , gene
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 ( Tb GSK3) 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 Tb GSK3 inhibitors. Following the hit validation process, we optimised a series of diaminothiazoles, identifying low‐nanomolar inhibitors of Tb GSK3 that are potent in vitro inhibitors of T. brucei proliferation. We show that the Tb GSK3 pharmacophore overlaps with that of one or more additional molecular targets.