Authors
M De Rycker2; M Thomas2; T Miles1; DDU Kinetoplastids Team2; P Wyatt2; J Fiandor-Roman2; D Gray2; K Read2; I Gilbert2; 1 GSK, Spain; 2 University of Dundee Discussion
The Drug Discovery Unit at the University of Dundee and the GlaxoSmithKline Kinetoplastid Discovery Performance Unit, with support from the Wellcome Trust, have formed a five year partnership to conduct drug discovery within kinetoplastid diseases. This collaboration has made significant progress, highlighted by the identification of a lead optimisation series for visceral leishmaniasis (VL). Here we describe the initial identification of the series through transitioning a Trypanosoma brucei active series into a VL active series. The series was profiled extensively in a panel of in vitro Leishmania assays including promastigote, axenic amastigote and intracellular assays as well as rate-of-kill and clinical isolate assays, an effort which helped us develop our Leishmania screening cascade. An overview of the lead-optimisation campaign will demonstrate how a focus on balancing potency and solubility eventually delivered a compound with candidate-level properties. Current standard of care for VL suffers from multiple issues (lack of efficacy, safety, drug resistance, stability, cost, parenteral administration only) and as a community there is a limited pipeline for VL. The new chemical series presented here is a significant step forward towards the development of a new oral drug for visceral leishmaniasis. This work illustrates the substantial benefits that working in an academic-industry partnership brings for the development of new drugs for neglected diseases. 
