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Discovery and mechanism of action studies of 4,6-diphenylpyrimidine-2-carbohydrazides as utrophin modulators for the treatment of Duchenne muscular dystrophy.
Vuorinen, Aini; Wilkinson, Isabel V L; Chatzopoulou, Maria; Edwards, Ben; Squire, Sarah E; Fairclough, Rebecca J; Bazan, Noelia Araujo; Milner, Josh A; Conole, Daniel; Donald, James R; Shah, Nandini; Willis, Nicky J; Martínez, R Fernando; Wilson, Francis X; Wynne, Graham M; Davies, Stephen G; Davies, Kay E; Russell, Angela J.
Afiliação
  • Vuorinen A; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK.
  • Wilkinson IVL; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK.
  • Chatzopoulou M; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK.
  • Edwards B; Department of Physiology, Anatomy and Genetics, University of Oxford, Sir Henry Wellcome Building of Gene Function, South Parks Road, Oxford, OX1 3PT, UK.
  • Squire SE; Department of Physiology, Anatomy and Genetics, University of Oxford, Sir Henry Wellcome Building of Gene Function, South Parks Road, Oxford, OX1 3PT, UK.
  • Fairclough RJ; Department of Physiology, Anatomy and Genetics, University of Oxford, Sir Henry Wellcome Building of Gene Function, South Parks Road, Oxford, OX1 3PT, UK.
  • Bazan NA; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK.
  • Milner JA; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK.
  • Conole D; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK.
  • Donald JR; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK.
  • Shah N; Department of Physiology, Anatomy and Genetics, University of Oxford, Sir Henry Wellcome Building of Gene Function, South Parks Road, Oxford, OX1 3PT, UK.
  • Willis NJ; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK.
  • Martínez RF; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK.
  • Wilson FX; Summit Therapeutics Plc, 136a Eastern Avenue, Milton Park, Abingdon, Oxfordshire, OX14 4SB, UK.
  • Wynne GM; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK.
  • Davies SG; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK.
  • Davies KE; Department of Physiology, Anatomy and Genetics, University of Oxford, Sir Henry Wellcome Building of Gene Function, South Parks Road, Oxford, OX1 3PT, UK. Electronic address: kay.davies@dpag.ox.ac.uk.
  • Russell AJ; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK; Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3PQ, UK. Electronic address: angela.russell@chem.ox.ac.uk.
Eur J Med Chem ; 220: 113431, 2021 Aug 05.
Article em En | MEDLINE | ID: mdl-33915371
ABSTRACT
Duchenne muscular dystrophy is a fatal disease with no cure, caused by lack of the cytoskeletal protein dystrophin. Upregulation of utrophin, a dystrophin paralogue, offers a potential therapy independent of mutation type. The failure of first-in-class utrophin modulator ezutromid/SMT C1100 in Phase II clinical trials necessitates development of compounds with better efficacy, physicochemical and ADME properties and/or complementary mechanisms. We have discovered and performed a preliminary optimisation of a novel class of utrophin modulators using an improved phenotypic screen, where reporter expression is derived from the full genomic context of the utrophin promoter. We further demonstrate through target deconvolution studies, including expression analysis and chemical proteomics, that this compound series operates via a novel mechanism of action, distinct from that of ezutromid.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article