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

  • Cell Chem Biol. 2024 Mar 19:S2451-9456(24)00087-4. doi: 10.1016/j.chembiol.2024.02.013.
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
Affiliations
  • 1. Bayer AG, Pharmaceuticals, Research & Development, Muellerstr. 178, 13353 Berlin, Germany; Nuvisan ICB GmbH, Muellerstr. 178, 13353 Berlin, Germany.
  • 2. Bayer AG, Pharmaceuticals, Research & Development, Muellerstr. 178, 13353 Berlin, Germany.
  • 3. Department of Molecular Medicine, University of Padua, Via Gabelli 63, 35121 Padua, Italy.
  • 4. Department of Molecular Medicine, University of Padua, Via Gabelli 63, 35121 Padua, Italy; IFOM, the FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy.
  • 5. Bayer AG, Pharmaceuticals, Research & Development, Muellerstr. 178, 13353 Berlin, Germany; Nuvisan ICB GmbH, Muellerstr. 178, 13353 Berlin, Germany. Electronic address: [email protected].
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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