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Identification of Inhibitors of the Leishmania cdc2-Related Protein Kinase CRK3
New drugs are urgently needed for the treatment of tropical parasitic diseases such as leishmaniasis and human African trypanosomiasis (HAT). This work involved a high-throughput screen of a focussed kinase set of ∼3400 compounds to identify potent and parasite-selective inhibitors of an enzymatic L...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
WILEY-VCH Verlag
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272345/ https://www.ncbi.nlm.nih.gov/pubmed/21913331 http://dx.doi.org/10.1002/cmdc.201100344 |
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author | Cleghorn, Laura A T Woodland, Andrew Collie, Iain T Torrie, Leah S Norcross, Neil Luksch, Torsten Mpamhanga, Chido Walker, Roderick G Mottram, Jeremy C Brenk, Ruth Frearson, Julie A Gilbert, Ian H Wyatt, Paul G |
author_facet | Cleghorn, Laura A T Woodland, Andrew Collie, Iain T Torrie, Leah S Norcross, Neil Luksch, Torsten Mpamhanga, Chido Walker, Roderick G Mottram, Jeremy C Brenk, Ruth Frearson, Julie A Gilbert, Ian H Wyatt, Paul G |
author_sort | Cleghorn, Laura A T |
collection | PubMed |
description | New drugs are urgently needed for the treatment of tropical parasitic diseases such as leishmaniasis and human African trypanosomiasis (HAT). This work involved a high-throughput screen of a focussed kinase set of ∼3400 compounds to identify potent and parasite-selective inhibitors of an enzymatic Leishmania CRK3–cyclin 6 complex. The aim of this study is to provide chemical validation that Leishmania CRK3–CYC6 is a drug target. Eight hit series were identified, of which four were followed up. The optimisation of these series using classical SAR studies afforded low-nanomolar CRK3 inhibitors with significant selectivity over the closely related human cyclin dependent kinase CDK2. |
format | Online Article Text |
id | pubmed-3272345 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | WILEY-VCH Verlag |
record_format | MEDLINE/PubMed |
spelling | pubmed-32723452012-02-06 Identification of Inhibitors of the Leishmania cdc2-Related Protein Kinase CRK3 Cleghorn, Laura A T Woodland, Andrew Collie, Iain T Torrie, Leah S Norcross, Neil Luksch, Torsten Mpamhanga, Chido Walker, Roderick G Mottram, Jeremy C Brenk, Ruth Frearson, Julie A Gilbert, Ian H Wyatt, Paul G ChemMedChem Full Papers New drugs are urgently needed for the treatment of tropical parasitic diseases such as leishmaniasis and human African trypanosomiasis (HAT). This work involved a high-throughput screen of a focussed kinase set of ∼3400 compounds to identify potent and parasite-selective inhibitors of an enzymatic Leishmania CRK3–cyclin 6 complex. The aim of this study is to provide chemical validation that Leishmania CRK3–CYC6 is a drug target. Eight hit series were identified, of which four were followed up. The optimisation of these series using classical SAR studies afforded low-nanomolar CRK3 inhibitors with significant selectivity over the closely related human cyclin dependent kinase CDK2. WILEY-VCH Verlag 2011-12-09 2011-09-13 /pmc/articles/PMC3272345/ /pubmed/21913331 http://dx.doi.org/10.1002/cmdc.201100344 Text en Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim http://creativecommons.org/licenses/by/2.5/ Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation. |
spellingShingle | Full Papers Cleghorn, Laura A T Woodland, Andrew Collie, Iain T Torrie, Leah S Norcross, Neil Luksch, Torsten Mpamhanga, Chido Walker, Roderick G Mottram, Jeremy C Brenk, Ruth Frearson, Julie A Gilbert, Ian H Wyatt, Paul G Identification of Inhibitors of the Leishmania cdc2-Related Protein Kinase CRK3 |
title | Identification of Inhibitors of the Leishmania cdc2-Related Protein Kinase CRK3 |
title_full | Identification of Inhibitors of the Leishmania cdc2-Related Protein Kinase CRK3 |
title_fullStr | Identification of Inhibitors of the Leishmania cdc2-Related Protein Kinase CRK3 |
title_full_unstemmed | Identification of Inhibitors of the Leishmania cdc2-Related Protein Kinase CRK3 |
title_short | Identification of Inhibitors of the Leishmania cdc2-Related Protein Kinase CRK3 |
title_sort | identification of inhibitors of the leishmania cdc2-related protein kinase crk3 |
topic | Full Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272345/ https://www.ncbi.nlm.nih.gov/pubmed/21913331 http://dx.doi.org/10.1002/cmdc.201100344 |
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