Abstract 4491: TY-0584: A potent, orally available small molecule YAP/TEAD inhibitor, exhibits anti-tumor effects in vitro and in vivo

Abstract Hippo/YAP pathway plays an essential role in cell proliferation, tissue regeneration, and tumorigenesis. The emerging evidence shows that hyperactivation of the Hippo/YAP pathway induces metastasis, chemoresistance, and the attribute of cancer stem cells. Dysregulated Hippo/YAP pathway can be a dominant driver of mesothelioma, meningioma, and schwannoma. It has been reported that Hippo/YAP oncogenic activation in mesothelioma is driven by NF2 loss function. In addition, it contributes to 10% of all cancers, including lung, gastric, colon, cervical, ovarian, breast, melanoma, hepatocellular, and squamous cell carcinoma. Despite the urgent need to develop a therapeutic strategy to curb the dysregulated pathway, YAP/TAZ is difficult to be directly targeted with small molecule inhibitors because of the lack of a catalytic niche. TEADs require auto-palmitoylation to become functional. Therefore, small molecules that target palmitoylation of TEAD have been explored and VT3989 (NCT04665206) and IK-930 (NCT05228015) have success to enter the clinical trials. To target cancers with dysregulated Hippo/Yap pathway, we have discovered and are developing TY-0584, which is a potent and orally available YAP/TEAD inhibitor in the IND enabling stage. The results of PK and toxicity studies of TY-0584 showed a favorable safety profile. TY-0584 had excellent efficacy in the malignant mesothelioma H226 CDX mouse model, which is driven by NF2 deletion mutation. TY-0584 treatment also demonstrated good efficacy in the head and neck cancer PDX tumor mouse model. In previous studies, Hippo/Yap signaling promotes drug resistance to EGFR-targeted therapies in non-small cell lung cancer (NSCLC). To relax the YAP resistance mechanism in EGFR treatment, we asked if combined YAP inhibition grants an extension of responses to EGFR therapy. To this end, we treated EGFR-driven NSCLC cell models with TY-0584 and TY-9591. TY-9591 is a third-generation EGFR inhibitor developed by TYK Medicines and is currently under a pivotal Phase III clinical investigation in China (NCT05382728). The results show that the combination treatment not only offers synergistic effects, but also enhances apoptosis, compared to single drug treatment. Our in vivo data further underscores this exciting finding. Our studies showed that TY-9591 had excellent efficacy in the PC9 CDX mouse model, but tumors gradually recurred as many targeted cancer therapies did. In line with the results of the in-vitro experiments, another YAP/TEAD inhibitor TY-0536 in combination with TY-9591 significantly delay the tumor regrowth in the PC9 CDX mouse model. In summary, we identified a potent and orally available YAP/TEAD inhibitor TY-0584 which is a promising candidate for further clinical validation. [Shengli Dong and Apeng Liang contributed equally to this work. Jun Li, Shengli Dong, and Apeng Liang are the corresponding authors.] Citation Format: Apeng Liang, Shengli Dong, Guangbin Liu, Zhengfei Guo, Meihua Li, Shuaibo Han, Yundi Cao, Yian Tu, Chao Zhou, Yu Yu, Linglin Xiao, Wei Huang, Xinlong Yang, Lian Fang, Haoyun Li, Chengshan Niu, Mingyu Jiang, Feng Xing, Shaoqing Chen, Jun Li, Yusheng Wu. TY-0584: A potent, orally available small molecule YAP/TEAD inhibitor, exhibits anti-tumor effects in vitro and in vivo. [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 4491.