MoA Studies of the TEAD P-Site Binding Ligand MSC-4106 and Its Optimization to TEAD1-Selective Amide M3686

  • J Med Chem. 2024 Dec 20. doi: 10.1021/acs.jmedchem.4c01949.
Timo Heinrich  1 ,  Daniel Schwarz  1 ,  Carl Petersson  1 ,  Jakub Gunera  1 ,  Sakshi Garg  1 ,  Richard Schneider  1 ,  Marina Keil  1 ,  Lisa Grimmeisen  1 ,  Andrea Unzue Lopez  1 ,  Lisa Albers  1 ,  Sarah Schlesiger  1 ,  Alessia Gambardella  1 ,  Joerg Bomke  1 ,  Emma Carswell  2 ,  Heike Schilke  1 ,  Patrizia Diehl  1 ,  Benjamin Doerfel  1 ,  Djordje Musil  1 ,  Elisabeth Trivier  3 ,  Rebecca Broome  3 ,  Sam Marshall  3 ,  Alexander Balsiger  3 ,  Erik Friedrich  1 ,  Ana R Lemos  4 ,  Sandra P Santos  4 ,  Pedro M F Sousa  4 ,  Filipe Freire  4 ,  Tiago M Bandeiras  4 ,  Alessio Bortoluzzi  4 ,  Dirk Wienke  1
Affiliations
  • 1. Merck Healthcare KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany.
  • 2. Cancer Research Horizons, Jonas Webb Building, Babraham Research Campus, CambridgeCB22 3AT, U.K.
  • 3. Cancer Research Horizons, 4NW, The Francis Crick Institute, 1 Midland Rd, London NW1 1AT, U.K.
  • 4. iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2781-901 Oeiras, Portugal.
PMID: 39704449 DOI: 10.1021/acs.jmedchem.4c01949
Abstract

Taking the structural information into account, we were able to tune the TEAD selectivity for a specific chemotype. However, different TEAD selectivity profiles did not affect the compound potency or efficacy in the NCI-H226 viability assay. Amides based on MSC-4106 or analogues showed improved viability efficacy compared with the corresponding acids. The amide M3686 exhibited AUC-driven efficacy in NCI-H226 xenograft models and had an improved 25-fold lower human dose prediction than MSC-4106. MSC-4106 was also used in HDX-MS studies to aid in the understanding of the MoA of P-site binding TEAD inhibitors. Artificial P-site Binders rigidify certain areas in the periphery of the transcription factor that seem to be crucial for cofactor interaction, whereas a native fatty acid increased the protein dynamics of cofactor-binding interfaces.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-170764
    M3686
    TEAD1/TEAD3 Inhibitor
    target: YAP
    Research Areas: Cancer