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

AUTHORS

Smith A , Wall RJ , Patterson S , Rowan T , Rico Vidal E , Stojanovski L , Huggett M , Hampton SE , Thomas MG , Corpas Lopez V , 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 F , Witty MJ , Wyllie S , Read KD , Gilbert IH , . Journal of medicinal chemistry. 2022 3 18; 65(7). 5606-5624

PMID: 35303411 [PubMed].

ABSTRACT

African animal trypanosomiasis or nagana, caused principally by infection of the protozoan parasites and 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 and 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.

Tags: alumni publications 2022