Markus Vögtle, Holger Sellner, Emilie A. Chapeau, Pascal Furet, Bahaâ Salem, Mickaël Le Douget, Vincent Bordas, Jean-Marc Groell, Anne-Laure Le Goff, Christine Rouzet, Thomas Wietlisbach, Thomas Zimmermann, Joseph P. McKenna, Cara E. Brocklehurst, Patrick Chène, Markus Wartmann, Clemens Scheufler, Jörg Kallen, Kanter Ruben de, Stephanie Harlfinger, Frédéric J. Zécri, Tobias Schmelzle, Nicolas Soldermann
The interaction of transcriptional enhanced associate domain (TEAD) and transcriptional coactivator yes-associated protein (YAP) mediates oncogenic functions downstream of the Hippo pathway. In this report, we outline our efforts to find a potent inhibitor of this protein-protein interaction with suitable properties for clinical evaluation. We detail the medicinal chemistry program that led to the discovery of IAG933, an inhibitor with a balanced ADME profile, enabling its evaluation as a potential treatment option in clinical settings.