2. Academic Validation
  3. Optimization of a Class of Dihydrobenzofurane Analogs toward Orally Efficacious YAP-TEAD Protein-Protein Interaction Inhibitors

Optimization of a Class of Dihydrobenzofurane Analogs toward Orally Efficacious YAP-TEAD Protein-Protein Interaction Inhibitors

  • ChemMedChem. 2023 Jun 1;18(11):e202300051. doi: 10.1002/cmdc.202300051.
Holger Sellner 1,  Emilie Chapeau 2,  Pascal Furet 1,  Markus Voegtle 1,  Bahaa Salem 1,  Mickaël Le Douget 1,  Vincent Bordas 1,  Jean-Marc Groell 1,  Anne-Laure Le Goff 1,  Christine Rouzet 1,  Thomas Wietlisbach 1,  Thomas Zimmermann 1,  Joseph McKenna 1,  Cara E Brocklehurst 1,  Patrick Chène 2,  Markus Wartmann 2,  Clemens Scheufler 3,  Joerg Kallen 3,  Gareth Williams 4,  Stephanie Harlfinger 4,  Martin Traebert 5,  Bérengère M Dumotier 5,  Tobias Schmelzle 2,  Nicolas Soldermann 1
Affiliations

Affiliations

  • 1 Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.
  • 2 Oncology Drug Discovery, Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.
  • 3 Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.
  • 4 Pharmacokinetics Sciences, Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.
  • 5 Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, 4002, Switzerland.
PMID: 36988034 DOI: 10.1002/cmdc.202300051
Abstract

The inhibition of the YAP-TEAD protein-protein interaction constitutes a promising therapeutic approach for the treatment of cancers linked to the dysregulation of the Hippo signaling pathway. The identification of a class of small molecules which potently inhibit the YAP-TEAD interaction by binding tightly to the Ω-loop pocket of TEAD has previously been communicated. This report details the further multi-parameter optimization of this class of compounds resulting in advanced analogs combining nanomolar cellular potency with a balanced ADME and off-target profile, and efficacy of these compounds in tumor bearing mice is demonstrated for the first time.

Keywords

PPI inhibitors; TEAD; YAP; in vivo efficacy; multi-parameter optimization.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-150256
    99.47%, YAP-TEAD Inhibitor
    YAP