2. Academic Validation
  3. Discovery and mechanism of action studies of 4,6-diphenylpyrimidine-2-carbohydrazides as utrophin modulators for the treatment of Duchenne muscular dystrophy

Discovery and mechanism of action studies of 4,6-diphenylpyrimidine-2-carbohydrazides as utrophin modulators for the treatment of Duchenne muscular dystrophy

  • Eur J Med Chem. 2021 Aug 5;220:113431. doi: 10.1016/j.ejmech.2021.113431.
Aini Vuorinen 1,  Isabel V L Wilkinson 1,  Maria Chatzopoulou 1,  Ben Edwards 2,  Sarah E Squire 2,  Rebecca J Fairclough 2,  Noelia Araujo Bazan 1,  Josh A Milner 1,  Daniel Conole 1,  James R Donald 1,  Nandini Shah 2,  Nicky J Willis 1,  R Fernando Martínez 1,  Francis X Wilson 3,  Graham M Wynne 1,  Stephen G Davies 1,  Kay E Davies 4,  Angela J Russell 5
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK.
  • 2 Department of Physiology, Anatomy and Genetics, University of Oxford, Sir Henry Wellcome Building of Gene Function, South Parks Road, Oxford, OX1 3PT, UK.
  • 3 Summit Therapeutics Plc, 136a Eastern Avenue, Milton Park, Abingdon, Oxfordshire, OX14 4SB, UK.
  • 4 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: [email protected].
  • 5 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: [email protected].
PMID: 33915371 DOI: 10.1016/j.ejmech.2021.113431
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.

Keywords

Chemical proteomics; Duchenne muscular dystrophy; Mechanism of action; Phenotypic drug discovery; Photoaffinity labelling; Target deconvolution; Utrophin.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-150078
    Utrophin Modulator