Abstract LB438: Discovery of a potent and selective pan-TEAD PROTAC directly targeting TEAD-YAP interaction with durable degradation activity

Abstract The Hippo signaling pathway is crucial for regulating numerous biological processes, and its dysregulation is associated with the development of various diseases. As a key effector of this pathway, the TEAD transcription factor interacts with its downstream co-activators YAP and TAZ when Hippo signaling is suppressed, thereby regulating genes involved in cell proliferation and apoptosis. While much research has focused on inhibiting TEAD's palmitoylation and disrupting its interaction with YAP, relatively few studies have explored TEAD-degrading agents. To address this gap, we designed and synthesized a series of heterobifunctional degraders targeting TEADs. Notably, the most prominent compound KG-FP-003 exhibited potent degradation activity, sustained for up to 7 days, and antiproliferative effects at nanomolar concentrations in MSTO-211H cells (lacking functional LATS1/2) and NCI-H226 cells (deficient in NF2), which is to our knowledge, the most effective TEAD degraders. Proteomic analysis revealed significant degradation of TEAD1 and TEAD4 in NCI-H226 cells and A172 cells, consistent with HiBiT assays. Additionally, using a CRBN-knockout MSTO-211H cell line, we demonstrated that KG-FP-003 promotes CRBN-dependent TEAD degradation in a dose-dependent manner. Concomitant with the loss of TEAD, we observed significant alternation of downstream transcription networks. Further studies revealed that KG-FP-003 was effective across a wide range of cell lines beyond mesothelioma. Its sensitivity profile correlates with the dependency scores of TEAD1,YAP1,JUN and TP53BP2. Moreover,KG-FP-003 significantly reduced the expression of key YAP target genes such as CYR61 and CTGF in solid tumors which outperforms known TEAD LBP inhibitors and PPI inhibitors in terms of antiproliferative activity. In summary, KG-FP-003 is a promising candidate for advancing the research of YAP-TEAD research and holds great potential for therapeutic development in Hippo pathway-related diseases. Citation Format: Kehao Zhao, Wenchao Lu, Linghui Cao, Yuhang Liu, Yufang Shi, Jian Chen, Yong Zhang. Discovery of a potent and selective pan-TEAD PROTAC directly targeting TEAD-YAP interaction with durable degradation activity [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 LB438.