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

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

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: martin.lange@nuvisan.com.
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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