Abstract 501: Discovery of BPI-460372, a potent and selective inhibitor of TEAD for the treatment of solid tumors harboring Hippo pathway aberrations

Abstract The Hippo signaling pathway is critical for the regulation of organ development, tissue homeostasis, and tumorigenesis by controlling the activation status of yes-associated protein (YAP) or its homolog PDZ-binding motif (TAZ). As a major downstream effector, the transcription factor TEAD is activated by forming a complex with YAP/TAZ. Hippo pathway aberrations, such as NF2-deficiency or LATS1/2 mutations leading to hyperactivation of YAP/TAZ and subsequent activation of TEAD, have been reported in many cancers, including mesothelioma, meningioma, soft tissue sarcoma and non-small cell lung cancer. Inhibiting TEAD auto-palmitoylation by directly blocking the palmitoylation pocket of TEAD is a potential therapeutic approach for cancer treatment. Here we present BPI-460372, a novel small molecule that directly blocks the TEAD auto-palmitoylation. BPI-460372 covalently and irreversibly binds to the cysteine residue in the TEAD palmitoylation pocket, preventing TEAD palmitoylation and inhibiting its biological function. BPI-460372 significantly inhibits the expression of a TEAD-responsive element reporter, as well as the mRNA of downstream target genes such as CTGF and CYR61 in NF2-deficient cells. At the cellular level, BPI-460372 strongly inhibited the proliferation of tumor cells harboring Hippo pathway aberrations. BPI-460372 also significantly suppressed tumor growth in NF2-deficient or LATS1/2 mutation xenograft models. In addition, BPI-460372 exhibited excellent oral bioavailability, high exposure across multiple species, and adequate ADME properties. In conclusion, BPI-460372 is a potent and selective TEAD palmitoylation inhibitor for the treatment of solid tumors harboring Hippo pathway aberrations. It is planned to enter Phase I clinical trial in China in early 2023. Citation Format: Hongling Shen, Xiaofeng Xu, Hongfei Rong, Xizhen Song, Jinheng Gao, Jie Chen, Di Zhu, Xiangdong Zhao, Jun Tong, Zhengyao Zou, Xiaoyun Liu, Jin Guo, Yan Xu, Yabin Li, Xiangyong Liu, Hong Chen, Jiayu Zhao, Yanju Liu, Xuepeng Ju, Haibo Chen, Hong Lan, Lieming Ding, Jiabing Wang. Discovery of BPI-460372, a potent and selective inhibitor of TEAD for the treatment of solid tumors harboring Hippo pathway aberrations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 501.