Article
作者: Eis, Knut ; Lakner, Ashley ; Font, Nuria Aiguabella ; Kuhnke, Lara ; Kopitz, Charlotte ; Ocker, Matthias ; Walter, Annette O ; von Nussbaum, Franz ; Pilari, Sabine ; Graham, Keith ; Bone, Wilhelm ; Nicke, Barbara ; Buchgraber, Philipp ; Kamburov, Atanas ; Montebaur, Anna ; Prechtl, Stefan ; Blotta, Simona ; Mumberg, Dominik ; Nowak-Reppel, Katrin ; Weiske, Joerg ; Zanconato, Francesca ; Lange, Martin ; Naujoks, Jan ; Piccolo, Stefano ; Hayat, Sikander ; Brzezinka, Krzysztof ; Potze, Lisette ; Kaulfuss, Stefan ; Golfier, Sven ; Lesche, Ralf ; Heinrich, Tobias ; Bader, Benjamin ; Steuber, Holger ; Steigemann, Patrick ; Stresemann, Carlo ; Braeuer, Nico ; Steffen, Andreas ; Lienau, Philip ; Schlicker, Andreas ; Kuehnlenz, Julia
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.
