Identification and characterization of hundreds of potent and selective inhibitors of Trypanosoma brucei growth from a kinase-targeted library screening campaign.

• Published in: PLoS Neglected Tropical Diseases
• Main Authors: Rosario Diaz, Sandra A Luengo-Arratta, João D Seixas, Emanuele Amata, William Devine, Carlos Cordon-Obras, Domingo I Rojas-Barros, Elena Jimenez, Fatima Ortega, Sabrinia Crouch, Gonzalo Colmenarejo, Jose Maria Fiandor, Jose Julio Martin, Manuela Berlanga, Silvia Gonzalez, Pilar Manzano, Miguel Navarro, Michael P Pollastri
• Format: Article in Journal/Newspaper
• Language: English
• Published: Public Library of Science (PLoS) 2014
• Subjects: Arctic medicine. Tropical medicine; RC955-962; Public aspects of medicine; RA1-1270; Arctic
• Online Access: https://doi.org/10.1371/journal.pntd.0003253; https://doaj.org/article/ea801c360d7c4780a126030ea3922d0e

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.