Abstract 4584: Novel YAP1/TAZ pathway inhibitors identified through phenotypic screening with potent anti-tumor activity via blockade of GGTase-I and Rho-GTPase signaling
Authors: Graham Keith , Lienau Philip , Bader Benjamin , Prechtl Stefan , Naujoks Jan , Lesche Ralf , Nicke Barbara , Bone Wilhelm , Golfier Sven , Brzezinka Krzysztof , Kaulfuss Stefan , Kopitz Charlotte , Steuber Holger , Braeuer Nico , Nowak-Reppel Katrin , Stresemann Carlo , Steigemann Patrick , Kuehnlenz Julia , Potze Lisette , Zanconato Francesca , Montebaur Anna , Pilari Sabine , Hayat Sikander , Kamburov Atanas , Steffen Andreas , Schlicker Andreas , Buchgraber Philipp , Font Nuria Aiguabella , Heinrich Tobias , Kuhnke Lara , Walter Annette O. , Blotta Simona , Ocker Matthias , Lakner Ashley , Mumberg Dominik , Eis Knut , Piccolo Stefano , Lange Martin 
Published: March 2024

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. 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. HTS hits that selectively inhibited TEAD-luciferase, but not TK-Renilla-luciferase (n = 3.994) were subsequently assessed regarding their ability to induce translocation of YAP1 from the nucleus to the cytoplasm in MDA-MB-231 cells, which is the physiological mechanism of inactivation. Out of these, 392 hits showed activity to induce translocation of YAP1. Finally, selected hits active in both assays (n = 96) were assessed regarding their effect on endogenous YAP1/TAZ target genes. The small molecule BAY-856 demonstrated the most consistent YAP1/TAZ inhibitory activity of all selected hits, which warranted further exploration of the unknown direct drug target. Target deconvolution studies identified the geranylgeranyltransferase-I (GGTase-I) complex, as the direct target of YAP1/TAZ pathway inhibitor BAY-856. BAY-856 and close analogs with improved in vitro potency blocked the activation of Rho-GTPases, leading to subsequent inactivation of YAP1/TAZ and inhibition of cancer cell proliferation in several tumor types in vitro. Multi-parameter optimization resulted in BAY-593, an in vivo probe with favorable PK properties. BAY-593 demonstrated anti-tumor activity in solid tumor models and blockade of YAP1/TAZ signaling in vivo. BAY-593 is a novel tool compound to explore Rho-GTPase signaling and downstream YAP1/TAZ biology in vitro and in vivo.

Citation Format: Keith Graham, Philip Lienau, Benjamin Bader, Stefan Prechtl, Jan Naujoks, Ralf Lesche, Barbara Nicke, Wilhelm Bone, Sven Golfier, Krzysztof Brzezinka, Stefan Kaulfuss, Charlotte Kopitz, Holger Steuber, Nico Braeuer, Katrin Nowak-Reppel, Carlo Stresemann, Patrick Steigemann, Julia Kuehnlenz, Lisette Potze, Francesca Zanconato, Anna Montebaur, Sabine Pilari, Sikander Hayat, Atanas Kamburov, Andreas Steffen, Andreas Schlicker, Philipp Buchgraber, Nuria Aiguabella Font, Tobias Heinrich, Lara Kuhnke, Annette O. Walter, Simona Blotta, Matthias Ocker, Ashley Lakner, Dominik Mumberg, Knut Eis, Stefano Piccolo, Martin Lange. Novel YAP1/TAZ pathway inhibitors identified through phenotypic screening with potent anti-tumor activity via blockade of GGTase-I and Rho-GTPase signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4584.