2. Academic Validation
  3. Phenotypic Hit Identification and Optimization of Novel Pan-TEAD and Subtype-Selective Inhibitors

Phenotypic Hit Identification and Optimization of Novel Pan-TEAD and Subtype-Selective Inhibitors

  • J Med Chem. 2025 Nov 27;68(22):24603-24623. doi: 10.1021/acs.jmedchem.5c02602.
Timo Heinrich 1,  Alessia Gambardella 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,  Heike Schilke 1,  Thomas Weitzel 1,  Christian Kolb 1,  Patrizia Diehl 1,  Benjamin Doerfel 1,  Uwe Anlauf 1,  Vivian Reither 1,  Corinna Rettig 1,  Beate Opelt 1,  Andrea Delp 1,  Nicole Wildner 1,  Djordje Musil 1,  Erik Friedrich 1,  Lars Burgdorf 1,  Thomas Fuchss 1,  Lisa Albers 1,  Pedro M F Sousa 2,  Filipe Freire 2,  Tiago M Bandeiras 2,  Dirk Wienke 1
Affiliations

Affiliations

  • 1 Merck Healthcare KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany.
  • 2 iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2781-901 Oeiras, Portugal.
PMID: 41212049 DOI: 10.1021/acs.jmedchem.5c02602
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 KRASG12C inhibitor sotorasib was demonstrated in vivo.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-179395
    TEAD抑制剂
    YAP
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