Repositioning of a Diaminothiazole Series Confirmed to Target the Cyclin-Dependent Kinase CRK12 for Use in the Treatment of African Animal Trypanosomiasis.

Smith, A; Wall, RJORCID logo; Patterson, S; Rowan, T; Rico Vidal, E; Stojanovski, L; Huggett, M; Hampton, SEORCID logo; Thomas, MGORCID logo; Corpas Lopez, V; +19 more...Gillingwater, K; Duke, J; Napier, G; Peter, R; Vitouley, HS; Harrison, JR; Milne, R; Jeacock, L; Baker, N; Davis, SH; Simeons, F; Riley, J; Horn, D; Brun, R; Zuccotto, FORCID logo; Witty, MJ; Wyllie, SORCID logo; Read, KDORCID logo; Gilbert, IHORCID logo and (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: 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.


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