Overview
TY-1054 is a novel, orally administered small-molecule inhibitor of transcriptional enhanced associate domain kinase (TEAD) that targets the Hippo signaling pathway. This compound was independently developed by TYK Medicines and is intended for the treatment of patients with solid tumors. The early studies of TY-1054 have demonstrated favorable antitumor efficacy and safety profiles. The compound is currently in the IND-enabling phase, and IND submissions are anticipated to be submitted to the FDA and NMPA in the fourth quarter of 2023.
Mechanism of Action
The Hippo/YAP signaling pathway functions in a manner that suppresses tumorigenesis, through the activation of transcriptional cofactors, namely Yes-associated protein (YAP) and the transcriptional co-activator with PDZ-binding motif (TAZ). These cofactors interact with transcriptional enhancer associated with TEAD to regulate gene expression. The Hippo/YAP pathway plays a critical role in processes such as cell proliferation, tissue regeneration, and oncogenesis. Dysregulation of the Hippo/YAP pathway has been implicated as a driving factor in the tumorigenesis of several cancers, including, mesothelioma, meningioma, and schwannoma. According to recent reports, roughly 60% of Mesothelioma cases are associated with the loss function of NF2 in the Hippo/YAP pathway, and the pathway is involved in approximately 10% of all cancers, including lung, gastric, colon, cervical cancer, breast, melanoma, hepatocellular, and squamous cell carcinoma. Directly targeting the YAP/TAZ pathway using small molecule inhibitors is challenging due to the lack of a catalytic niche, as well as the requirement for auto-palmitoylation of TEAD. As a result, there is a pressing need to develop alternative treatments for dysregulation of the Hippo/YAP pathway.
Furthermore, there is evidence to suggest that the Hippo/YAP signaling pathway promotes drug resistance to EGFR-targeted therapies in NSCLC patients, making YAP inhibitors a potential strategy for overcoming the drug resistance to EGFR-targeted therapies.
