Discovery Of Novel Potent Allosteric Inhibitors Of Yap/Taz-Tead Transcription For The Treatment Of Multiple Solid Tumor Types Addicted To Hippo Signaling

The Hippo pathway is a highly conserved signaling pathway across higher-order vertebrates and a key modulator of developmental biology. Both genetic aberrations as well as non-genetic dysregulation of the pathway lead to constitutive nuclear localization and transcriptional activity of the YAP/TAZ-TEAD complex in multiple solid tumor types, including mesothelioma, uveal melanoma, squamous cell cancer, liver cancer, lung cancer, etc. Genetic aberrations are manifested as gene amplifications and gene fusions of the core transcriptional YAP/TAZ-TEAD complex subunits, and, more commonly, as deletions or loss-of-function mutations in the upstream negative regulators of the Hippo pathway such as NF2, LATS1/2 or FAT1. More recently, constitutive activation of YAP/TAZ-TEAD has been implicated in cancer therapy resistance and in immune evasion. Multiple efforts have been devoted to identify small-molecule inhibitors of the YAP/TAZ-TEAD protein-protein interaction, yet with limited success reported to date. Based on the identification of an auto-palmitoylation pocket centrally located in TEAD, and its reported role to sustain YAP/TAZ-TEAD transcriptional activity, we set up a biophysical assay to detect selective small-molecule binding into the palmitoylation pocket of TEAD1. Based on screening a rationally designed compound collection in this assay and iterations of analoging, we identified several novel chemical series of TEAD-palmitoylation pocket binders. Hits were confirmed as specific allosteric inhibitors of YAP/TAZ-TEAD transcription in cell-based assays (Q-PCR and reporter gene assays). Soaking compounds in TEAD crystals revealed structural information enabling hit-to-lead optimization of two different chemical series. Best allosteric inhibitors in the series display single-digit nM potency in transcriptional assays, and translate to low nM inhibition of Hippo mutant (but not WT, \u003e1000x selectivity window) mesothelioma proliferation. These molecules are well suited to probe for additional Hippo-dependent solid cancer types using in vitro cancer cell panels, selected based on genetics and/or a YAP/TAZ-TEAD gene signature. Furthermore, optimization towards orally bioavailable compounds is in progress and an update on in vivo efficacy in various solid tumor models will be presented. Citation Format: Matthias Versele, Aurelie Candi, Marnik Nijs, Wanda Haeck, Hugo Klaassen, Wim Smets, Stephane Spieser, Bart Vanderhoydonck, Arnaud Marchand, Patrick Chaltin, Leticia Sansores, Georg Halder. Discovery of novel potent allosteric inhibitors of YAP/TAZ-TEAD transcription for the treatment of multiple solid tumor types addicted to Hippo signaling [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5229.