Abstract B116: Robust efficacy and favorable safety profile of pan-TEAD inhibitors in oncogenic Hippo pathway-dysregulated cancers including mesothelioma

Abstract The Hippo pathway regulates cell proliferation and tissue homeostasis through a YAP/TAZ-TEAD transcriptional complex. Alterations in this pathway often lead to constitutive YAP/TAZ-TEAD activation, driving aberrant expression of target genes like CTGF and CYR61. These alterations are commonly found in various cancers due to genetic mutations or oncogenic pathway crosstalk, contributing to tumorigenesis and drug resistance in malignancies such as mesothelioma, meningioma, head and neck squamous cell carcinoma (HNSCC) non-small cell lung cancer (NSCLC) and so on. TEAD activation depends on auto-palmitoylation, an essential process for its function, making its inhibition a promising therapeutic strategy. Although YAP/TAZ–TEAD inhibitors targeting auto-palmitoylation are actively being developed, improving both the potency and safety of current treatments remains a critical unmet medical need. Therefore, developing YAP/TAZ–TEAD inhibitors that target palmitoylation with an improved safety profile is essential as a novel anticancer strategy for tumors driven by dysregulated Hippo signaling. We developed a series of novel small-molecule inhibitors targeting the palmitate-binding pocket (PBP), that disrupt the formation of the YAP/TAZ-TEAD complex. These inhibitors exhibited high potency, with IC50 values below 10 nM in a TEAD-luciferase reporter assay. Our compounds, potent pan-TEAD inhibitors with balanced activity, disrupted the palmitoylation of TEAD1–4 isoforms in a cell-free system using a click-chemistry-based assay. In addition, our candidates induced dose-dependent growth inhibition in Hippo pathway–altered cancer cell lines and suppressed YAP/TAZ–TEAD transcriptional target genes such as CTGF and CYR61. In mesothelioma xenograft models with hippo pathway alterations, these TEAD inhibitors resulted in a significant reduction of tumor growth and downregulated mRNA expression levels of target genes, which are recognized as pharmacodynamic markers. Furthermore, at the daily efficacious dose, the compounds caused no significant change in urinary albumin levels in NCI-H226 xenograft mice, thereby leading to an overall highly favorable pharmacological and safety profile. In summary, we identified novel TEAD inhibitors that demonstrated robust efficacy in both in vitro and in vivo xenograft models of cancers with Hippo pathway alterations. Our candidates demonstrated low-grade proteinuria in preclinical models, indicating a favorable safety profile with respect to nephrotoxicity. These findings highlight the potential of our optimized TEAD inhibitor as a therapeutic agent for cancers characterized by genetic alterations in Hippo signaling pathway. Comprehensive preclinical results will be disclosed upon the nomination of a development candidate. Citation Format: Jisook Kim, Chunghoon Shin, Jisu Yun, Youngkyo Jeon, Suho Kim, Heesun Moon, Hobin Im, Jooyun Byun, Seung Hyun Jung, Young Gil Ahn. Robust efficacy and favorable safety profile of pan-TEAD inhibitors in oncogenic Hippo pathway-dysregulated cancers including mesothelioma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B116.