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research
Identification and Characterization of Hundreds of Potent and Selective Inhibitors of Trypanosoma brucei Growth from a Kinase-Targeted Library Screening Campaign
Authors
Emanuele Amata
M. Berlanga
+16 more
Gonzalo Colmenarejo
Carlos Cordon-Obras
Sabrinia Crouch
William Devine
Rosa Diaz
José M. Fiandor
S. Gonzalez
Elena Jimenez
Sandra A. Luengo-Arratta
Pilar Manzano
José Julio Martin
M. Navarro
F. Ortega
M.P. Pollastri
Domingo I. Rojas-Barros
Joao D. Seixas
Publication date
25 February 2015
Publisher
'Public Library of Science (PLoS)'
Doi
Cite
Abstract
© 2014 Diaz et al. In the interest of identification of new kinase-targeting chemotypes for target and pathway analysis and drug discovery in Trypanosomal brucei, a high-throughput screen of 42,444 focused inhibitors from the GlaxoSmithKline screening collection was performed against parasite cell cultures and counter-screened against human hepatocarcinoma (HepG2) cells. In this way, we have identified 797 sub-micromolar inhibitors of T. brucei growth that are at least 100-fold selective over HepG2 cells. Importantly, 242 of these hit compounds acted rapidly in inhibiting cellular growth, 137 showed rapid cidality. A variety of in silico and in vitro physicochemical and drug metabolism properties were assessed, and human kinase selectivity data were obtained, and, based on these data, we prioritized three compounds for pharmacokinetic assessment and demonstrated parasitological cure of a murine bloodstream infection of T. brucei rhodesiense with one of these compounds (NEU-1053). This work represents a successful implementation of a unique industrial-academic collaboration model aimed at identification of high quality inhibitors that will provide the parasitology community with chemical matter that can be utilized to develop kinase-targeting tool compounds. Furthermore these results are expected to provide rich starting points for discovery of kinase-targeting tool compounds for T. brucei, and new HAT therapeutics discovery programs.Peer Reviewe
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Last time updated on 25/05/2016