Novel YAP1/TAZ pathway inhibitors identified through phenotypic screening with potent anti-tumor activity via blockade of GGTase-I / Rho-GTPase signaling

This study describes the identification and target deconvolution of novel small molecule inhibitors of oncogenic 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 novel 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 . SIGNIFICANCE YAP1/TAZ have been shown to be aberrantly activated oncogenes in several human solid tumors, resulting in enhanced cell proliferation, metastasis and provision of a pro-tumorigenic microenvironment, making YAP1/TAZ targets for novel cancer therapies. Yet, the development of effective inhibitors of these potent oncogenes has been challenging. In this work, we break new ground in this direction through the identification of novel inhibitors of YAP1/TAZ activity. ![Figure][1] HIGHLIGHTS ### Competing Interest Statement K. Graham, B. Bader, S. Prechtl, J. Naujoks, R. Lesche, K. Brzezinka, B. Nicke, W. Bone, S. Golfier, S. Kaulfuss, C. Kopitz, H. Steuber, N. Braeuer, K. Nowak-Reppel, C. Stresemann, P. Steigemann, M. Lange are / were employees of Nuvisan ICB GmbH and Bayer Pharma AG. P. Lienau, J. Kuehnlenz, L. Potze, A. Montebaur, S. Pilari, S. Hayat, A. Kamburov, A. Steffen, A. Schlicker, P. Buchgraber, N. A. Font, T. Heinrich, L. Kuhnke, A.O. Walter, S. Blotta, M. Ocker, A. Lakner, D. Mumberg, K. Eis are / were employees of Bayer Pharma AG. This studies was funded by Bayer Pharma AG. The following patent applications in relation to this study have been submitted: WO-2020048826-A1, WO-2020048830-A1, WO-2020048829-A1, WO-2020048828-A1, WO-2020048831-A1, WO-2020048827-A1. S. Piccolo served as consultant for Bayer AG in relation to these studies. [1]: pending:yes