Abstract 4585: Discovery of ETS-006, a highly potent YAP/TEADs PPI inhibitor with broad anti-tumor activity as a single agent

Abstract The transcription co-activators YAP, pairing with the TEAD family of transcription factors, serve as essential effectors of the conserved Hippo signaling pathway. Hippo kinase cascade controls YAP nuclear entry and binding with TEADs by modulating its phosphorylation and stability. Overexpression and activation of YAP/TAZ are frequently observed in a variety of cancers. It has been well established that YAP aberration contributes to cancer development, metastasis, immunosurveillance escape and drug resistance. Disruption of YAP/TEADs PPI is an effective approach to inhibit YAP transcriptional activity. We previously have reported the identification of YAP/TEADs PPI hit compound through the fragment-based screen and advanced the hit to lead compound ETS-003. Here we reported the preclinical candidate of YAP/TEADs PPI inhibitor ETS-006 with much more potent anti-tumor activity and favorable safety profile. Compared to TEAD palmitoylation inhibitor, ETS-006 could completely disrupt the interaction of YAP/TEADs, resulting in a more profound downregulation of YAP target gene expression. ETS-006 demonstrated more robust anti-tumor activity than the competitor’s YAP/TEADs PPI inhibitor in MPM CDX model with favorable ADME properties. Notably, ETS-006 showed promising efficacy across multiple solid tumor types, including head and neck squamous cell carcinoma, osteosarcoma, and triple-negative breast cancer with urgent unmet clinical needs. In conclusion, ETS-006 is a highly potent and orally available YAP/TEADs PPI inhibitor with broad anti-tumor activity as a single agent. Citation Format: Jiajun Lu, Ming Gao, Wenpei Du, Xiaofei Fan, Jinping Li, Mengya Wang, Lijian Feng, Yingjie Li, Jiaqi Yao, Jiting Lu, Wenqi Cui, Qiangang Zheng, Jidong Zhu. Discovery of ETS-006, a highly potent YAP/TEADs PPI inhibitor with broad anti-tumor activity as a single agent abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4585.