Journal of medicinal chemistry · 2022
Repositioning of a Diaminothiazole Series Confirmed to Target the Cyclin-Dependent Kinase CRK12 for Use in the Treatment of African Animal Trypanosomiasis.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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, 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
Аннотация
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.