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
  • 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.
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-150256
    YTP-17
    98.04%, YAP-TEAD Inhibitor
    target: YAP
    Research Areas: Cancer