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Design of a Potent, Selective, and Brain-Penetrant Inhibitor of Wnt-Deactivating Enzyme Notum by Optimization of a Crystallographic Fragment Hit.
Willis, Nicky J; Mahy, William; Sipthorp, James; Zhao, Yuguang; Woodward, Hannah L; Atkinson, Benjamin N; Bayle, Elliott D; Svensson, Fredrik; Frew, Sarah; Jeganathan, Fiona; Monaghan, Amy; Benvegnù, Stefano; Jolly, Sarah; Vecchia, Luca; Ruza, Reinis R; Kjær, Svend; Howell, Steven; Snijders, Ambrosius P; Bictash, Magda; Salinas, Patricia C; Vincent, Jean-Paul; Jones, E Yvonne; Whiting, Paul; Fish, Paul V.
Afiliación
  • Willis NJ; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, U.K.
  • Mahy W; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, U.K.
  • Sipthorp J; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, U.K.
  • Zhao Y; The Francis Crick Institute, 1 Midland Road, Kings Cross, London NW1 1AT, U.K.
  • Woodward HL; Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Roosevelt Drive, Oxford OX3 7BN, U.K.
  • Atkinson BN; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, U.K.
  • Bayle ED; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, U.K.
  • Svensson F; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, U.K.
  • Frew S; The Francis Crick Institute, 1 Midland Road, Kings Cross, London NW1 1AT, U.K.
  • Jeganathan F; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, U.K.
  • Monaghan A; The Francis Crick Institute, 1 Midland Road, Kings Cross, London NW1 1AT, U.K.
  • Benvegnù S; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, U.K.
  • Jolly S; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, U.K.
  • Vecchia L; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, U.K.
  • Ruza RR; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, U.K.
  • Kjær S; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, U.K.
  • Howell S; Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Roosevelt Drive, Oxford OX3 7BN, U.K.
  • Snijders AP; Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Roosevelt Drive, Oxford OX3 7BN, U.K.
  • Bictash M; The Francis Crick Institute, 1 Midland Road, Kings Cross, London NW1 1AT, U.K.
  • Salinas PC; The Francis Crick Institute, 1 Midland Road, Kings Cross, London NW1 1AT, U.K.
  • Vincent JP; The Francis Crick Institute, 1 Midland Road, Kings Cross, London NW1 1AT, U.K.
  • Jones EY; Alzheimer's Research UK UCL Drug Discovery Institute, University College London, Cruciform Building, Gower Street, London WC1E 6BT, U.K.
  • Whiting P; Department of Cell and Developmental Biology, Laboratory for Molecular and Cellular Biology, University College London, London WC1E 6BT, U.K.
  • Fish PV; The Francis Crick Institute, 1 Midland Road, Kings Cross, London NW1 1AT, U.K.
J Med Chem ; 65(10): 7212-7230, 2022 05 26.
Article en En | MEDLINE | ID: mdl-35536179
Notum is a carboxylesterase that suppresses Wnt signaling through deacylation of an essential palmitoleate group on Wnt proteins. There is a growing understanding of the role Notum plays in human diseases such as colorectal cancer and Alzheimer's disease, supporting the need to discover improved inhibitors, especially for use in models of neurodegeneration. Here, we have described the discovery and profile of 8l (ARUK3001185) as a potent, selective, and brain-penetrant inhibitor of Notum activity suitable for oral dosing in rodent models of disease. Crystallographic fragment screening of the Diamond-SGC Poised Library for binding to Notum, supported by a biochemical enzyme assay to rank inhibition activity, identified 6a and 6b as a pair of outstanding hits. Fragment development of 6 delivered 8l that restored Wnt signaling in the presence of Notum in a cell-based reporter assay. Assessment in pharmacology screens showed 8l to be selective against serine hydrolases, kinases, and drug targets.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores Enzimáticos / Esterasas Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2022 Tipo del documento: Article
Texto completo
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XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores Enzimáticos / Esterasas Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2022 Tipo del documento: Article