9S64

Human TEAD1 in complex with 2-(4-chloro-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H-pyrrolo[3,2-c]pyridin-1-yl)ethan-1-ol

This is a non-PDB format compatible entry.

Summary for 9S64

• Entry DOI: 10.2210/pdb9s64/pdb
• Descriptor: Transcriptional enhancer factor TEF-1, MYRISTIC ACID, GLYCEROL, ... (6 entities in total)
• Functional Keywords: inhibitor, mesothelioma tumor regression transcription, transcription regulation, transcription-protei binding complex, transcription
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 103321.87

Authors

Musil, D.,Freire, F. (deposition date: 2025-07-30, release date: 2026-02-04)

Primary citation

Heinrich, T.,Gambardella, A.,Schwarz, D.,Petersson, C.,Gunera, J.,Garg, S.,Schneider, R.,Keil, M.,Grimmeisen, L.,Unzue Lopez, A.,Schilke, H.,Weitzel, T.,Kolb, C.,Diehl, P.,Doerfel, B.,Anlauf, U.,Reither, V.,Rettig, C.,Opelt, B.,Delp, A.,Wildner, N.,Musil, D.,Friedrich, E.,Burgdorf, L.,Fuchss, T.,Albers, L.,Sousa, P.M.F.,Freire, F.,M Bandeiras, T.,Wienke, D.
Phenotypic Hit Identification and Optimization of Novel Pan-TEAD and Subtype-Selective Inhibitors.
J.Med.Chem., 68:24603-24623, 2025

PubMed Abstract: Aiming to identify novel inhibitors of YAP-TEAD-dependent transcription, we conducted a TEAD-reporter-based cellular screen, which yielded a 5-azaindole hit that significantly stabilized TEAD subtypes 2 and 4 in a thermal shift assay. During optimization, derivatives with diverse TEAD selectivity profiles were obtained, including pan-TEAD and TEAD3-sparing inhibitors. Atropisomers with stabilized binding conformations surprisingly resulted in TEAD2 selective inhibitors. Cellular potency in reporter and viability assays was enhanced through targeted structural modifications. The physicochemical and pharmacokinetic properties were improved by the introduction of heteroatoms and the reduction of aromaticity. Structure-based considerations inspired the generation of a pyrrolo-pyridinone scaffold with further optimized properties. In lung cancer xenograft studies, representatives from both substance classes demonstrated monotherapeutic antitumor activity. For one selected example, the combination effect with the KRAS inhibitor was demonstrated in vivo.

PubMed: 41212049
DOI: 10.1021/acs.jmedchem.5c02602

Experimental method

X-RAY DIFFRACTION (1.85 Å)