Abstract LB238: Expanding the TEAD therapeutic potential with degraders: In vitro sensitivity, predictive biomarkers, and in vivo efficacy

Abstract TEAD transcription factors have emerged as clinically validated targets for cancers with dysregulated Hippo signaling, such as mesothelioma driven by NF2 inactivation or deficiency. We have developed a series of novel small-molecule targeted protein degraders of TEAD, designed to bind to TEAD interface 3. These compounds function by forming a ternary complex with the E3 ligase cereblon in cells, resulting in the ubiquitination and subsequent proteasomal degradation of TEAD. P65-047, one of these degraders, was evaluated using a large-scale cellular PRISM (Profiling Relative Inhibition Simultaneously in Mixtures) screen, which revealed sensitivity in a select subset of cell lines beyond mesothelioma. Univariate analysis of the PRISM sensitivity profile and genomic features identified VGLL3 gene expression as the strongest association. A multivariate gene expression biomarker analysis yielded a model that can predict cell line sensitivity to P65-047 (AUC = 0.82). Unlike the more well-known coactivators YAP and TAZ, which bind simultaneously to interfaces 1, 2, and 3, VGLL3 is a TEAD coactivator that binds only to interfaces 1 and 2. Additional findings from lineage enrichments and multivariate biomarker analysis will also be discussed. In pharmacokinetic experiments conducted in mice, intraperitoneal administration of P65-047 resulted in high exposure in both plasma and lung tissue. A dose-dependent degradation of TEAD1 was observed in lung tissue 24 hours after a single dose, with the compound being well tolerated and with no signs of toxicity. P65-047 was further tested in a mouse CDX model of mesothelioma using the NF2-deficient cell line NCI-H226. The results of this study will be discussed. Citation Format: Rajiv Sawant, Matthis Geitmann, Thomas Gossas, Wei B. Emond, Ulf Bremberg, Konrad Koehler, Melissa M. Ronan, Matthew G. Rees, Jennifer A. Roth, Peter Brandt. Expanding the TEAD therapeutic potential with degraders: In vitro sensitivity, predictive biomarkers, and in vivo efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB238.