Abstract B142: Discovery of novel and potent TEAD inhibitors, orally available small molecules with anti-tumor activity in hippo pathway- dysregulated cancers
Abstract
Hippo pathway plays a critical role in cell apoptosis, proliferation, tissue homeostasis. Dysregulation of Hippo pathway was reported to related to overall aspects of tumorigenesis. The higher expression a YAP/TAZ and TEADs or mutation of core components of hippo pathway, such as NF2, MST1/2 and LATS1/2 were reported in various cancer subtypes including mesothelioma, meningioma, glioblastoma, non-small cell lung cancer. TEAD auto-palmitoylation is required for protein stability and its transcriptional activity. Inhibiting TEAD activity regulation present attractive strategy for therapeutic intervention in the Hippo pathway. There are increasing proof that the inhibitor to central pocket of TEAD can be promising candidate for cancer treatment. We validated and optimized the hits, derived from our in silico screening system. Our lead compounds inhibiting palmitoylation of TEADs are the potent in vitro activities in TEAD reporter assay and hippo pathway-dysregulated mesotheliomas. In addition, these compounds reduced the expression of TEAD target genes. Furthermore, our compounds strongly inhibited tumor growth in NF2 deficient mouse xenograft model without any adverse events. In these models, our compounds showed excellent PK-PD correlation. Using these compounds, we also tested the possibility as therapy for combination drugs with KRAS inhibitor, EGFR inhibitors. In summary, we have potent TEAD inhibitor series, that showed inhibitory activities of tumor growth in NF2…
Read the paper
Related studies
- Challenges and opportunities with drug repurposing: finding strategies to find alternative uses of therapeutics
- Challenges in Chagas Disease Drug Development
- T Cell Specificity: A Great Challenge in Chagas Disease
- Benznidazole treatment leads to DNA damage in Trypanosoma cruzi and the persistence of rare widely dispersed non-replicative amastigotes in mice
- Rapid Molecular Detection of Terbinafine-resistant Dermatophytes
- Identifying novel drugs with new modes of action for neglected tropical fungal skin diseases (fungal skinNTDs) using an Open Source Drug discovery approach
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.