Sellner, Holger, Chapeau, Emilie, Furet, Pascal, Voegtle, Markus, Le Douget, Mickael, Bordas, Vincent, Le Goff, Anne-Laure, Rouzet, Christine, Wietlisbach, Thomas, Brocklehurst, Cara, Chene, Patrick, Wartmann, Markus, Scheufler, Clemens, Williams, Gareth, Traebert, Martin, Dumotier, Berengere, Schmelzle, Tobias, Soldermann, Nicolas and Zimmermann, Thomas (2023) Optimization of a Class of Dihydrobenzofurane Analogs Toward Orally Efficacious YAP-TEAD Protein-Protein Interaction Inhibitors. ChemMedChem : chemistry enabling drug discovery.

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.

Item Type:	Article
Keywords:	optimization of cellular potency, ADME and PK properties; reduction of cardiac ion channel inhibition; in vivo efficacy in mice
Date Deposited:	12 Apr 2023 00:45
Last Modified:	12 Apr 2023 00:45
URI:	https://oak.novartis.com/id/eprint/49577