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

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.