Kinase inhibitors have been implicated in biological processes for a multitude of diseases, including cancer, infectious diseases, and viral infections. In response to repeated calls for new treatments for neglected tropical diseases we screened some 42,444-kinase inhibitor chemotypes in collaboration with GlaxoSmithKline. This approach is directed at repurposing established knowledge about classes of molecular targets that the pathogen and humans hold in common, recognizing that the huge body of historical knowledge around homologous targets could be quickly redirected to inhibiting pathogen growth.<br/>This presentation will cover one hit-to-lead program stemming from that screening campaign that is representative of our philosophy; through the synthesis of 49 derivatives we ascertained the structure-activity relationships, improving potency for the pathogen, and selectivity versus mammalian cell lines. Our advanced lead compound was curative in the in vivo systemic model of human African trypanosomiasis infection, but was unsuccessful in the CNS model of the disease. As part of our program we also screened these compounds against other kinetoplastid parasites that cause Chagas disease and leishmaniasis, tested against the fluke responsible for schistosomiasis, as well as the pathogenic free-living amoeba that cause granulomatous amoebic encephalitis. This has led to the identification of separate structure-activity relationship streams and affords us the opportunity to develop unique therapeutics for multiple disease-causing pathogens.

Kinase inhibitor chemotypes affords opportunities to target multiple disease-causing parasites

ACS Spring 2022

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