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. 2024 Jul 18;31(7):1247-1263.e16.
doi: 10.1016/j.chembiol.2024.02.013. Epub 2024 Mar 26.

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

Keith Graham  1 , Philip Lienau  2 , Benjamin Bader  1 , Stefan Prechtl  1 , Jan Naujoks  1 , Ralf Lesche  1 , Joerg Weiske  1 , Julia Kuehnlenz  2 , Krzysztof Brzezinka  1 , Lisette Potze  2 , Francesca Zanconato  3 , Barbara Nicke  1 , Anna Montebaur  2 , Wilhelm Bone  1 , Sven Golfier  1 , Stefan Kaulfuss  1 , Charlotte Kopitz  1 , Sabine Pilari  2 , Holger Steuber  1 , Sikander Hayat  2 , Atanas Kamburov  2 , Andreas Steffen  2 , Andreas Schlicker  2 , Philipp Buchgraber  2 , Nico Braeuer  1 , Nuria Aiguabella Font  2 , Tobias Heinrich  2 , Lara Kuhnke  2 , Katrin Nowak-Reppel  1 , Carlo Stresemann  1 , Patrick Steigemann  1 , Annette O Walter  2 , Simona Blotta  2 , Matthias Ocker  2 , Ashley Lakner  2 , Franz von Nussbaum  1 , Dominik Mumberg  2 , Knut Eis  2 , Stefano Piccolo  4 , Martin Lange  5
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Free article

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

Keith Graham et al. Cell Chem Biol. .
Free article

Abstract

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.

Keywords: Rho-GTPase; TEAD; YAP1/TAZ; small molecule inhibitor.

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Conflict of interest statement

Declaration of interests K.G., B.B, S.P., J.N., J.W., R.L., K.B, B.N., W.B., S.G., S.K., C.K., H.S., N.B., K.N-R., C.S., P.S., M.L. are/were employees of Nuvisan ICB GmbH and Bayer Pharma AG. P.L., J.K., L.P., A.M., S.P., S.H., A.K., A.St., A.Sc., P.B., N.A.F., T.H., L.K., A.O.W., S.B., M.O., A. L., F.v.N., D.M., K.E. are/were employees of Bayer Pharma AG. This study 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.P. served as consultant for Bayer in relation to this study.

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