2. Academic Validation
  3. Towards the design of ligands of the internal pocket TEADs C-terminal domain

Towards the design of ligands of the internal pocket TEADs C-terminal domain

  • Eur J Med Chem. 2025 Jan 15:282:117026. doi: 10.1016/j.ejmech.2024.117026.
Florine Toulotte 1,  Mathilde Coevoet 1,  Maxime Liberelle 1,  Fabrice Bailly 1,  Benjamin Zagiel 1,  Muriel Gelin 2,  Frédéric Allemand 2,  Patrick Fourquet 3,  Patricia Melnyk 4,  Jean-François Guichou 5,  Philippe Cotelle 6
Affiliations

Affiliations

  • 1 Univ Lille, INSERM, CHU Lille, UMR-S 1172, Lille Neuroscience and Cognition Research Center, F-59000, Lille, France.
  • 2 Centre de Biologie Structurale (CBS), CNRS, INSERM, Univ Montpellier, F-34090, Montpellier, France.
  • 3 Centre de Recherche en Cancérologie de Marseille (CRCM), CNRS, INSERM, Marseille Protéomique, Institut Paoli-Calmettes, Aix Marseille University, 27 Bvd Leï Roure, CS 30059, 13273 Marseille, France.
  • 4 Univ Lille, INSERM, CHU Lille, UMR-S 1172, Lille Neuroscience and Cognition Research Center, F-59000, Lille, France. Electronic address: patricia.melnyk@univ-lille.fr.
  • 5 Centre de Biologie Structurale (CBS), CNRS, INSERM, Univ Montpellier, F-34090, Montpellier, France. Electronic address: guichou@cbs.cnrs.fr.
  • 6 Univ Lille, INSERM, CHU Lille, UMR-S 1172, Lille Neuroscience and Cognition Research Center, F-59000, Lille, France; ENSCL-Centrale Lille, CS 90108, F-59652, Villeneuve d'Ascq, France.
PMID: 39571457 DOI: 10.1016/j.ejmech.2024.117026
Abstract

The Hippo pathway controls in organ size and tissue homeostasis through regulating cell growth, proliferation and Apoptosis. Phosphorylation of the transcription co-activator YAP (Yes associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif) regulates their nuclear import and therefore their interaction with TEAD (Transcriptional Enhanced Associated Domain). YAP, TAZ and TEADs are dysregulated in several solid cancers making YAP/TAZ-TEAD interaction a new anti-cancer target. We identified by screening a small in-house library, 5-benzyloxindole which binds to hTEAD2 at its internal/palmitate pocket. Its optimization led to covalent inhibitors bearing different warhead. Soaking with hTEAD2 gave seven new crystal structures where the ligands occupied palmitate pocket. 5-Benzyloxyindoles armed with vinylsulfamide moiety inhibit YAP/TAZ-TEAD target genes expression and breast Cancer cell proliferation at micromolar concentration.

Keywords

Breast cancer proliferation inhibition; Hippo pathway; TEAD inhibition; TEAD internal pocket.

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