Repositioning of a Diaminothiazole Series Confirmed to Target the Cyclin-Dependent Kinase CRK12 for Use in the Treatment of African Animal Trypanosomiasis.
Smith, Alasdair;
Wall, Richard J;
Patterson, Stephen;
Rowan, Tim;
Rico Vidal, Eva;
Stojanovski, Laste;
Huggett, Margaret;
Hampton, Shahienaz E;
Thomas, Michael G;
Corpas Lopez, Victoriano;
+19 more...Gillingwater, Kirsten;
Duke, Jeff;
Napier, Grant;
Peter, Rose;
Vitouley, Hervé S;
Harrison, Justin R;
Milne, Rachel;
Jeacock, Laura;
Baker, Nicola;
Davis, Susan H;
Simeons, Frederick;
Riley, Jennifer;
Horn, David;
Brun, Reto;
Zuccotto, Fabio;
Witty, Michael J;
Wyllie, Susan;
Read, Kevin D;
Gilbert, Ian H;
(2022)
Repositioning of a Diaminothiazole Series Confirmed to Target the Cyclin-Dependent Kinase CRK12 for Use in the Treatment of African Animal Trypanosomiasis.
Journal of medicinal chemistry, 65 (7).
pp. 5606-5624.
ISSN 0022-2623
DOI: https://doi.org/10.1021/acs.jmedchem.1c02104
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African animal trypanosomiasis or nagana, caused principally by infection of the protozoan parasites Trypanosoma congolense and Trypanosoma vivax, is a major problem in cattle and other livestocks in sub-Saharan Africa. Current treatments are threatened by the emergence of drug resistance and there is an urgent need for new, effective drugs. Here, we report the repositioning of a compound series initially developed for the treatment of human African trypanosomiasis. A medicinal chemistry program, focused on deriving more soluble analogues, led to development of a lead compound capable of curing cattle infected with both T. congolense and T. vivax via intravenous dosing. Further optimization has the potential to yield a single-dose intramuscular treatment for this disease. Comprehensive mode of action studies revealed that the molecular target of this promising compound and related analogues is the cyclin-dependent kinase CRK12.
