Authors

C Cordon-Obras¹; R Diaz Gonzalez¹; G Perez-Moreno¹; C Bosch-Navarrete¹; B Martinez-Arribas¹; LM Ruiz-Pérez¹; MP Pollastri²; AB Dounay³; L Ferrins²; D Gonzalez-Pacanowska¹;  ¹ Instituto de Parasitología y Biomedicina López-Neyra (IPBLN-CSIC), Spain;  ² Northeastern University, College of Sciences, United States;  ³ Colorado College, United States

Discussion

Kinase inhibitors have been described as a tool for rapid compound progression in the discovery of new treatments against parasitic diseases. We present data aimed at target identification for a series of compound classes with anti-kinetoplastid activity and potential kinase inhibitory activity. ERK8 and GSK3b, belonging to the CMGC superfamily of kinases, are known validated targets for therapeutic purposes in kinetoplastids. Existing data point towards these two kinases as potential targets of the selected compound clusters. Recombinant purified TbERK8 and TcGSK3b were obtained and the in vitro inhibition profiles of the two enzymes were established. In vitro assays were also performed with HsGSK3b for assessment of enzyme selectivity. Moreover, we generated a T. brucei line over-expressing TbERK8 and exposed it to a selected set of inhibitors. Kinase over-expression causes a severe growth defect in the parasite upon induction. This toxicity is reverted in a dose dependent manner by certain TbERK8 inhibitors, suggesting that the over-expressed kinase is the main target for this subset of compounds.