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A survey of the kinome pharmacopeia reveals multiple scaffolds and targets for the development of novel anthelmintics.
Knox, Jessica; Joly, Nicolas; Linossi, Edmond M; Carmona-Negrón, José A; Jura, Natalia; Pintard, Lionel; Zuercher, William; Roy, Peter J.
Afiliación
  • Knox J; Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
  • Joly N; The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, M5S 3E1, Canada.
  • Linossi EM; Programme Équipe Labellisée Ligue Contre Le Cancer, Institut Jacques Monod, UMR7592, Université de Paris, CNRS, Paris, France.
  • Carmona-Negrón JA; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, 94158, USA.
  • Jura N; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, 94158, USA.
  • Pintard L; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, 94158, USA.
  • Zuercher W; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, 94158, USA.
  • Roy PJ; Programme Équipe Labellisée Ligue Contre Le Cancer, Institut Jacques Monod, UMR7592, Université de Paris, CNRS, Paris, France.
Sci Rep ; 11(1): 9161, 2021 04 28.
Article en En | MEDLINE | ID: mdl-33911106
Over one billion people are currently infected with a parasitic nematode. Symptoms can include anemia, malnutrition, developmental delay, and in severe cases, death. Resistance is emerging to the anthelmintics currently used to treat nematode infection, prompting the need to develop new anthelmintics. Towards this end, we identified a set of kinases that may be targeted in a nematode-selective manner. We first screened 2040 inhibitors of vertebrate kinases for those that impair the model nematode Caenorhabditis elegans. By determining whether the terminal phenotype induced by each kinase inhibitor matched that of the predicted target mutant in C. elegans, we identified 17 druggable nematode kinase targets. Of these, we found that nematode EGFR, MEK1, and PLK1 kinases have diverged from vertebrates within their drug-binding pocket. For each of these targets, we identified small molecule scaffolds that may be further modified to develop nematode-selective inhibitors. Nematode EGFR, MEK1, and PLK1 therefore represent key targets for the development of new anthelmintic medicines.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Caenorhabditis elegans / Inhibidores de Proteínas Quinasas / Evaluación Preclínica de Medicamentos / Antihelmínticos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Sci Rep Año: 2021 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Caenorhabditis elegans / Inhibidores de Proteínas Quinasas / Evaluación Preclínica de Medicamentos / Antihelmínticos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Sci Rep Año: 2021 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Reino Unido