Project description:Purpose: The goal of this study is to understand the signaling pathway alteration in NCI-H226 cells treated with new TEAD autopalmitoylation inhibitor TM2, and to further validate TEAD inhibitor for specifity in TEAD-YAP interuption. Methods: Mesothelioma cell line NCI-H226 was chosen to be treated with TEAD palmitoylation inhibitor TM2 at 1μM for 24 hours. Total RNA was isolated for the analysis. RNA samples were sent to Novogen for library construction, RNA sequencing and raw data process. Conclusions: Our study privides gene expression profiling evidence to validate our TEAD palmitoylation inhibitor TM2 as specific small molecule to block TEAD transcriptional activity in mesothelioma cells.
Project description:Purpose: The goal of this study is to understand the signaling pathway alteration in NCI-H226 cells treated with TEAD inhibitors. Methods: Mesothelioma cell line NCI-H226 was chosen to be treated with TEAD inhibitors at 1μM for 24 hours. Total RNA was isolated for the analysis. RNA samples were sent to Novogen for library construction, RNA sequencing and raw data process. Conclusions: Our study privides gene expression profiling evidence to validate TEAD inhibitors to block TEAD transcriptional activity in mesothelioma cells.
Project description:We investigate the dependence of human malignant mesothelioma on functional TEAD transcription factors to maintain fully established tumors in vivo. We show that TEAD inhibitor K-975 stops tumor growth in vivo, eventually causing tumor regression, by downregulating TEAD activity and altering, thus, TEAD-dependent transcription in a dysfunctional Hippo genetic background. Our data validate the concept of inhibiting an activated YAP1/TEAD complex for the treatment of malignant pleural mesothelioma patients.
Project description:We measured chromatin accessibility using ATAC-sequencing for MCF-7 cells treated with vehicle (DMSO), GDC-9545 or GNE-858. GNE-858 is a non-ER degrader (SERM) from the same chemical series as GDC-9545.
Project description:TEAD proteins are a family of transcription factors that enable the oncogenic activity of deregulated Hippo signaling and are a promising therapeutic target in oncology. Targeting the lipid pocket of TEAD is an established path to inhibit the oncogenic activities of the cofactors YAP and TAZ. Here we present two covalent pan-TEAD inhibitors that bind to the lipid pocket, GNE-8025 and GNE-2181. GNE-8025 binds TEAD proteins covalently at a conserved cysteine residue to engage the lipid pocket and allosterically disrupt the interaction of TEAD proteins with YAP. GNE-2181 is a further optimized version of GNE-8025 with properties that enable brain penetrance in vivo. Both of these small molecules suppress the proliferation of YAP-driven tumor cells both in vitro and in vivo and increase activity of a broad range of inhibitors of the MAPK pathway. We demonstrate that these molecules have exceptional efficacy in Hippo-driven in vivo tumor models, including in a mouse model of brain metastases where GNE-2181 treatment significantly inhibits the growth of intracranial brain tumors. Altogether we present a next-generation class of TEAD inhibitors. The development of GNE-8025 and GNE-2181 is a significant advancement towards potent, specific, and effective Hippo-targeting cancer therapies.
