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

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-170764
    TEAD1/TEAD3 Inhibitor
    YAP