Article
作者: Weiske, Joerg ; Steuber, Holger ; Bader, Benjamin ; Graham, Keith ; Lienau, Philip ; Golfier, Sven ; Lange, Martin ; Prechtl, Stefan ; Bone, Wilhelm ; Lesche, Ralf ; Blotta, Simona ; Schlicker, Andreas ; Eis, Knut ; Pilari, Sabine ; Piccolo, Stefano ; Braeuer, Nico ; Kuehnlenz, Julia ; Naujoks, Jan ; Nicke, Barbara ; Kuhnke, Lara ; Kaulfuss, Stefan ; Font, Nuria Aiguabella ; Montebaur, Anna ; Potze, Lisette ; Nowak-Reppel, Katrin ; Buchgraber, Philipp ; Kopitz, Charlotte ; Mumberg, Dominik ; Zanconato, Francesca ; Steffen, Andreas ; Steigemann, Patrick ; Ocker, Matthias ; Heinrich, Tobias ; von Nussbaum, Franz ; Stresemann, Carlo ; Brzezinka, Krzysztof ; Lakner, Ashley ; Walter, Annette O ; Hayat, Sikander ; Kamburov, Atanas
This study describes the identification and target deconvolution of small molecule inhibitors of oncogenic Yes-associated protein (YAP1)/TAZ activity with potent anti-tumor activity in vivo. A high-throughput screen (HTS) of 3.8 million compounds was conducted using a cellular YAP1/TAZ reporter assay. Target deconvolution studies identified the geranylgeranyltransferase-I (GGTase-I) complex as the direct target of YAP1/TAZ pathway inhibitors. The small molecule inhibitors block the activation of Rho-GTPases, leading to subsequent inactivation of YAP1/TAZ and inhibition of cancer cell proliferation in vitro. Multi-parameter optimization resulted in BAY-593, an in vivo probe with favorable PK properties, which demonstrated anti-tumor activity and blockade of YAP1/TAZ signaling in vivo.
