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Identification and Characterization of Hundreds of Potent and Selective Inhibitors of Trypanosoma brucei Growth from a Kinase-Targeted Library Screening Campaign

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...

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Autores principales: Diaz, Rosario, Luengo-Arratta, Sandra A., Seixas, João D., Amata, Emanuele, Devine, William, Cordon-Obras, Carlos, Rojas-Barros, Domingo I., Jimenez, Elena, Ortega, Fatima, Crouch, Sabrinia, Colmenarejo, Gonzalo, Fiandor, Jose Maria, Martin, Jose Julio, Berlanga, Manuela, Gonzalez, Silvia, Manzano, Pilar, Navarro, Miguel, Pollastri, Michael P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207660/
https://www.ncbi.nlm.nih.gov/pubmed/25340575
http://dx.doi.org/10.1371/journal.pntd.0003253
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author Diaz, Rosario
Luengo-Arratta, Sandra A.
Seixas, João D.
Amata, Emanuele
Devine, William
Cordon-Obras, Carlos
Rojas-Barros, Domingo I.
Jimenez, Elena
Ortega, Fatima
Crouch, Sabrinia
Colmenarejo, Gonzalo
Fiandor, Jose Maria
Martin, Jose Julio
Berlanga, Manuela
Gonzalez, Silvia
Manzano, Pilar
Navarro, Miguel
Pollastri, Michael P.
author_facet Diaz, Rosario
Luengo-Arratta, Sandra A.
Seixas, João D.
Amata, Emanuele
Devine, William
Cordon-Obras, Carlos
Rojas-Barros, Domingo I.
Jimenez, Elena
Ortega, Fatima
Crouch, Sabrinia
Colmenarejo, Gonzalo
Fiandor, Jose Maria
Martin, Jose Julio
Berlanga, Manuela
Gonzalez, Silvia
Manzano, Pilar
Navarro, Miguel
Pollastri, Michael P.
author_sort Diaz, Rosario
collection PubMed
description 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.
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spelling pubmed-42076602014-10-27 Identification and Characterization of Hundreds of Potent and Selective Inhibitors of Trypanosoma brucei Growth from a Kinase-Targeted Library Screening Campaign Diaz, Rosario Luengo-Arratta, Sandra A. Seixas, João D. Amata, Emanuele Devine, William Cordon-Obras, Carlos Rojas-Barros, Domingo I. Jimenez, Elena Ortega, Fatima Crouch, Sabrinia Colmenarejo, Gonzalo Fiandor, Jose Maria Martin, Jose Julio Berlanga, Manuela Gonzalez, Silvia Manzano, Pilar Navarro, Miguel Pollastri, Michael P. PLoS Negl Trop Dis Research Article 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. Public Library of Science 2014-10-23 /pmc/articles/PMC4207660/ /pubmed/25340575 http://dx.doi.org/10.1371/journal.pntd.0003253 Text en © 2014 Diaz et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Diaz, Rosario
Luengo-Arratta, Sandra A.
Seixas, João D.
Amata, Emanuele
Devine, William
Cordon-Obras, Carlos
Rojas-Barros, Domingo I.
Jimenez, Elena
Ortega, Fatima
Crouch, Sabrinia
Colmenarejo, Gonzalo
Fiandor, Jose Maria
Martin, Jose Julio
Berlanga, Manuela
Gonzalez, Silvia
Manzano, Pilar
Navarro, Miguel
Pollastri, Michael P.
Identification and Characterization of Hundreds of Potent and Selective Inhibitors of Trypanosoma brucei Growth from a Kinase-Targeted Library Screening Campaign
title Identification and Characterization of Hundreds of Potent and Selective Inhibitors of Trypanosoma brucei Growth from a Kinase-Targeted Library Screening Campaign
title_full Identification and Characterization of Hundreds of Potent and Selective Inhibitors of Trypanosoma brucei Growth from a Kinase-Targeted Library Screening Campaign
title_fullStr Identification and Characterization of Hundreds of Potent and Selective Inhibitors of Trypanosoma brucei Growth from a Kinase-Targeted Library Screening Campaign
title_full_unstemmed Identification and Characterization of Hundreds of Potent and Selective Inhibitors of Trypanosoma brucei Growth from a Kinase-Targeted Library Screening Campaign
title_short Identification and Characterization of Hundreds of Potent and Selective Inhibitors of Trypanosoma brucei Growth from a Kinase-Targeted Library Screening Campaign
title_sort identification and characterization of hundreds of potent and selective inhibitors of trypanosoma brucei growth from a kinase-targeted library screening campaign
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207660/
https://www.ncbi.nlm.nih.gov/pubmed/25340575
http://dx.doi.org/10.1371/journal.pntd.0003253
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