title: Identification and characterization of hundreds of potent and selective inhibitors of Trypanosoma brucei growth from a kinase-targeted library screening campaign.
abstract: 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.
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra" Consejo Superior de Investigaciones Cientificas, Granada, Spain.
authors.forename: Rosario
authors.initials: R
authors.lastname: Diaz
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra" Consejo Superior de Investigaciones Cientificas, Granada, Spain; Department of Chemistry and Chemical Biology and Center for Drug Discovery, Northeastern University, Boston, Massachusetts, United States of America.
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Luengo-Arratta
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra" Consejo Superior de Investigaciones Cientificas, Granada, Spain; Department of Chemistry and Chemical Biology and Center for Drug Discovery, Northeastern University, Boston, Massachusetts, United States of America.
authors.forename: João D
authors.initials: JD
authors.lastname: Seixas
authors.affiliation: Department of Chemistry and Chemical Biology and Center for Drug Discovery, Northeastern University, Boston, Massachusetts, United States of America.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Amata
authors.affiliation: Department of Chemistry and Chemical Biology and Center for Drug Discovery, Northeastern University, Boston, Massachusetts, United States of America.
authors.forename: William
authors.initials: W
authors.lastname: Devine
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra" Consejo Superior de Investigaciones Cientificas, Granada, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Obras
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra" Consejo Superior de Investigaciones Cientificas, Granada, Spain.
authors.forename: Domingo I
authors.initials: DI
authors.lastname: Rojas-Barros
authors.affiliation: Tres Cantos Medicines Development Campus, DDW and CIB, GlaxoSmithKline, Tres Cantos, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Jimenez
authors.affiliation: Tres Cantos Medicines Development Campus, DDW and CIB, GlaxoSmithKline, Tres Cantos, Spain.
authors.forename: Fatima
authors.initials: F
authors.lastname: Ortega
authors.affiliation: Tres Cantos Medicines Development Campus, DDW and CIB, GlaxoSmithKline, Tres Cantos, Spain.
authors.forename: Sabrinia
authors.initials: S
authors.lastname: Crouch
authors.affiliation: Tres Cantos Medicines Development Campus, DDW and CIB, GlaxoSmithKline, Tres Cantos, Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Colmenarejo
authors.affiliation: Tres Cantos Medicines Development Campus, DDW and CIB, GlaxoSmithKline, Tres Cantos, Spain.
authors.forename: Jose Maria
authors.initials: JM
authors.lastname: Fiandor
authors.affiliation: Tres Cantos Medicines Development Campus, DDW and CIB, GlaxoSmithKline, Tres Cantos, Spain.
authors.forename: Jose Julio
authors.initials: JJ
authors.lastname: Martin
authors.affiliation: Tres Cantos Medicines Development Campus, DDW and CIB, GlaxoSmithKline, Tres Cantos, Spain.
authors.forename: Manuela
authors.initials: M
authors.lastname: Berlanga
authors.affiliation: Tres Cantos Medicines Development Campus, DDW and CIB, GlaxoSmithKline, Tres Cantos, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Gonzalez
authors.affiliation: Tres Cantos Medicines Development Campus, DDW and CIB, GlaxoSmithKline, Tres Cantos, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Manzano
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra" Consejo Superior de Investigaciones Cientificas, Granada, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Navarro
authors.affiliation: Department of Chemistry and Chemical Biology and Center for Drug Discovery, Northeastern University, Boston, Massachusetts, United States of America.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Pollastri
mesh_terms: D000818:Animals; D055808:Drug Discovery; D005260:Female; D056945:Hep G2 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000254:growth & development; D014353:Trypanosomiasis, African / Q000188:drug therapy
chemical_list: D047428:Protein Kinase Inhibitors; D014344:Trypanocidal Agents