MoA Studies of the TEAD P-Site Binding Ligand MSC-4106 and Its Optimization to TEAD1-Selective Amide M3686
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 <b>MSC-4106</b> or analogues showed improved viability efficacy compared with the corresponding acids. The amide <b>M3686</b> exhibited AUC-driven efficacy in NCI-H226 xenograft models and had an improved 25-fold lower human dose prediction than <b>MSC-4106</b>. <b>MSC-4106</b> 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.
Authors
- Filipe Freire (ORCID: https://orcid.org/0000-0002-5310-0668)
- Sandra P. Santos (ORCID: https://orcid.org/0000-0001-9153-5550)
- Marina Keil (ORCID: https://orcid.org/0009-0004-1799-2912)
- Pedro M. F. Sousa (ORCID: https://orcid.org/0000-0002-6672-3610)
- Dirk Wienke
- Ana R. Lemos (ORCID: https://orcid.org/0000-0002-3987-4771)
- Emma L. Carswell
- Stephen Marshall (ORCID: https://orcid.org/0000-0001-7678-4989)
- Erik Friedrich (ORCID: https://orcid.org/0000-0003-0173-1190)
- Benjamin Doerfel
- Alexander Balsiger
- Jakub Gunera
- Timo Heinrich (ORCID: https://orcid.org/0000-0001-9120-8410)
- Dániel Schwarz (ORCID: https://orcid.org/0000-0002-9017-8245)
- Tiago M. Bandeiras (ORCID: https://orcid.org/0000-0001-6089-6089)
- Sarah Schlesiger (ORCID: https://orcid.org/0000-0001-7880-3936)
- Patrizia Diehl
- Alessia Gambardella (ORCID: https://orcid.org/0009-0008-2113-619X)
- Andrea Unzue Lopez
- Alessio Bortoluzzi (ORCID: https://orcid.org/0009-0000-1027-8784)
- Joerg Bomke
- Heike Schilke
- Elisabeth Trivier
- Carl Petersson (ORCID: https://orcid.org/0000-0003-2560-9560)
- Sakshi Garg (ORCID: https://orcid.org/0000-0001-8662-5949)
- Rebecca Broome
- Djordje Müsil (ORCID: https://orcid.org/0000-0001-7889-2940)
- Richard Schneider
- Lisa Albers
- Lisa Grimmeisen
Institutions
- Babraham Institute (GB)
- Merck KGaA, Darmstadt (Germany) (DE)
- The Francis Crick Institute (GB)
- Instituto de Biologia Experimental e Tecnológica (PT)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-12-20
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01949
- Citations
- 9
- Primary Topic
- Hippo pathway signaling and YAP/TAZ
- Type
- article
- Field-Weighted Citation Impact
- 2.93