Phenotypic Hit Identification and Optimization of Novel Pan-TEAD and Subtype-Selective Inhibitors
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<sup>G12C</sup> inhibitor <b>sotorasib</b> was demonstrated in vivo.
Authors
- Filipe Freire (ORCID: https://orcid.org/0000-0002-5310-0668)
- Marina Keil (ORCID: https://orcid.org/0009-0004-1799-2912)
- Corinna Rettig
- Pedro M. F. Sousa (ORCID: https://orcid.org/0000-0002-6672-3610)
- Dirk Wienke
- Vivian Reither
- Uwe Anlauf
- Erik Friedrich (ORCID: https://orcid.org/0000-0003-0173-1190)
- Thomas Weitzel (ORCID: https://orcid.org/0000-0002-9804-2123)
- Benjamin Doerfel
- Jakub Gunera
- Lars T. Burgdorf
- Axel Delp
- 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)
- C. E. Kolb (ORCID: https://orcid.org/0000-0002-3138-5455)
- Patrizia Diehl
- Alessia Gambardella (ORCID: https://orcid.org/0009-0008-2113-619X)
- Thomas Fuchß (ORCID: https://orcid.org/0000-0002-1203-7180)
- Andrea Unzue Lopez
- Heike Schilke
- Sakshi Garg (ORCID: https://orcid.org/0000-0001-8662-5949)
- Djordje Müsil (ORCID: https://orcid.org/0000-0001-7889-2940)
- Richard Schneider
- Carl Petersson
- Lisa Albers
- Lisa Grimmeisen
- Beate Opelt
- Nicole Wildner
Institutions
- Merck KGaA, Darmstadt (Germany) (DE)
- Instituto de Biologia Experimental e Tecnológica (PT)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-11-10
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02602
- Citations
- 1
- Primary Topic
- Hippo pathway signaling and YAP/TAZ
- Type
- article
- Field-Weighted Citation Impact
- 1.15