Repurposing GSK-3 Inhibitors for Kinetoplastids

Status
Completed
Start date
End date
Start stage
Screening
End stage
Screening
Disease
Chagas disease
Leishmaniasis
Human African trypanosomiasis (HAT)
Research areas
Drug

Dr. Wyatt leads the Drug Discovery Unit at the University of Dundee, and was interested in repurposing GSK-3 beta inhibitors for treating kinetoplastid diseases. BVGH connected Dr. Wyatt with AstraZeneca, who shared a targeted library of nine GSK-3 inhibitors with him. Dr. Wyatt tested the inhibitors for activity against T. cruzi, T. brucei, and Leishmania. A compound with interesting activity against L. donovani was identified and AstraZeneca provided 1000 analogues for testing in the University of Dundee assays. Structure release was agreed for 10 of the most promising analogues and any available PK information was provided by AstraZeneca, as well as kinase panel selectivity data. One compound had a promising profile and AstraZeneca provided 200mg of this compound to allow an in vivo efficacy study for visceral leishmaniasis at the University of Dundee. While this compound showed some level of efficacy it also had toxic side effects. Currently this program is progressing at the University of Dundee with its main aim improving the selectivity of the series.