# Potent kinase inhibitors from the Merck KGaA OGHL: Novel hits against Trypanosoma brucei with potential for repurposing

## TL;DR

Researchers identified three new kinase inhibitors from a Merck compound library that show strong activity against the parasite causing African trypanosomiasis.

## Contribution

Discovery of three potent and selective kinase inhibitors with potential for drug repurposing against Trypanosoma brucei.

## Key findings

- Three compounds (OGHL00006, OGHL00133, OGHL00169) showed low micromolar to nanomolar IC50 values against Trypanosoma brucei.
- OGHL00006 and OGHL00169 caused rapid and irreversible growth arrest in the parasite.
- Molecular modeling suggests these compounds inhibit key kinases in the parasite's growth and survival.

## Abstract

African trypanosomiasis remains a critical public health concern, with over 55 million people still at risk of infection. There are several issues associated with the current therapies including toxicity and resistance, which represent the main bottleneck of trypanosomiasis control. Thus, it is urgent to develop novel therapeutic tools with distinct mechanisms of action. The in vitro phenotypic screening of the Merck KGaA Darmstadt German Open Global Health Library (OGHL) against Trypanosoma brucei brucei yielded three potent kinase inhibitors belonging to different chemical series: a phenylcarbonylacrylamide (OGHL00006); a 2,4-di(phenylamino)pyrimidine (OGHL00133); and a 3-(triazol-4-yl)-7-azaindole (OGHL00169). They exhibited low micromolar to nanomolar median inhibitory concentrations (IC50 values of 0.6 µM, 0.007 µM, and 0.25 µM, respectively) and good selectivity when tested on Vero cells (SI > 2). OGHL00006 and OGHL00169 induced a rapid and irreversible growth arrest of T. b. brucei within 4–24 hours of incubation. Interestingly, these two hits have also been reported to display antiplasmodial and/or anthelminthic activities, hinting at a similar mechanism of action across multiple species. Given the significant sequence similarities between the human and trypanosome kinomes, we rationalized the putative mechanisms of action for the identified hits through comparative modeling of protein–ligand complexes. This study suggests promising avenues for drug and/or target repurposing against trypanosomiasis.

African trypanosomiasis is a parasitic disease caused by parasites of the Trypanosoma brucei species, affecting both human and animal health thereby hindering socio-economic development in endemic countries. Current antitrypanosomal therapies are compromised by issues of drug resistance and toxicity. Moreover, in contrast to the progress made in the treatment of human trypanosomiasis, no new drug has been developed for animal trypanosomiasis in several decades, highlighting an urgent need for novel therapeutic options. Given the high cost, length and complexity of conventional drug development, repurposing existing compounds has become a widely adopted strategy in drug discovery. In this study, we performed an antitrypanosomal screening of the Merck KGaA Darmstadt Germany Open Global Health Library and identified three promising and non-toxic compounds: OGHL00006, OGHL00133 and OGHL00169. Subsequent investigations demonstrated that only OGHL00006 and OGHL00169 exhibit trypanocidal activity. Molecular modelling further revealed that these two compounds inhibit key Trypanosomes kinases involved in parasite growth and survival. This study uncovers two potential lead compounds offering promising candidates for the development of new therapies against African trypanosomiasis.