Abstract LB029: Degraders of TEAD transcription factors based on interface 3 binders

Abstract TEAD transcription factors have emerged as clinically validated targets for Hippo-altered cancers, e.g. mesothelioma driven by NF2 inactivation/deficiency. We have developed a series of novel small molecule targeted protein degraders of TEAD based on pan-TEAD interface 3 ligands. In cells, the compounds induce degradation of TEAD by formation of a ternary complex with Cereblon, leading to ubiquitination of TEAD and subsequent proteasomal degradation. In a cell-based luciferase reporter assay the degraders show low nanomolar activity. The downstream effects of TEAD degradation were further investigated by qPCR and WB analyses of bona fide YAP-TEAD target genes such as CTGF, Cyr61 and AMOTL2. The effectiveness of the TEAD degraders were compared to other classes of TEAD modulators such as palmitoylation inhibitors and YAP-TEAD protein-protein inhibitors by means of cellular viability assays using various mesothelioma cell lines. Finally, we performed an unbiased, quantitative high-throughput drug combination screening by combining a TEAD degrader with a library of approximately 2,800 oncology-focused drugs. This research was supported in part by the Intramural/Extramural research program of the NCATS, NIH. Citation Format: Rajiv Sawant, Matthis Geitmann, Thomas Gossas, Wei B. Emond, Ulf Bremberg, Konrad Koehler, Michele Ceribelli, Craig J. Thomas, Peter Brandt. Degraders of TEAD transcription factors based on interface 3 binders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB029.