9GAX

TEAD1 in complex with a reversible inhibitor N-[(1S)-2-hydroxy-1-(1-methyl-1H-pyrazol-3-yl)ethyl]-2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxamide

This is a non-PDB format compatible entry.

Summary for 9GAX

• Entry DOI: 10.2210/pdb9gax/pdb
• Descriptor: Transcriptional enhancer factor TEF-1, GLYCEROL, 2-methyl-~{N}-[(1~{S})-1-(1-methylpyrazol-3-yl)-2-oxidanyl-ethyl]-4-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indole-7-carboxamide, ... (5 entities in total)
• Functional Keywords: irreversible covalent inhibitor, mesothelioma tumor regression, transcription, transcription regulation, transcription-protein binding complex
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 52647.42

Authors

Musil, D.,Freire, F. (deposition date: 2024-07-29, release date: 2025-01-22, Last modification date: 2025-04-09)

Primary citation

Heinrich, T.,Schwarz, D.,Petersson, C.,Gunera, J.,Garg, S.,Schneider, R.,Keil, M.,Grimmeisen, L.,Unzue Lopez, A.,Albers, L.,Schlesiger, S.,Gambardella, A.,Bomke, J.,Carswell, E.,Schilke, H.,Diehl, P.,Doerfel, B.,Musil, D.,Trivier, E.,Broome, R.,Marshall, S.,Balsiger, A.,Friedrich, E.,Lemos, A.R.,Santos, S.P.,Sousa, P.M.F.,Freire, F.,Bandeiras, T.M.,Bortoluzzi, A.,Wienke, D.
MoA Studies of the TEAD P-Site Binding Ligand MSC-4106 and Its Optimization to TEAD1-Selective Amide M3686.
J.Med.Chem., 68:6149-6164, 2025

PubMed 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 or analogues showed improved viability efficacy compared with the corresponding acids. The amide exhibited AUC-driven efficacy in NCI-H226 xenograft models and had an improved 25-fold lower human dose prediction than . 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.

PubMed: 39704449
DOI: 10.1021/acs.jmedchem.4c01949

Experimental method

X-RAY DIFFRACTION (1.93 Å)