The Multi-Faceted Landscape of TEAD Inhibition: a 2017-2025 Patent and Literature Review.

TEAD (Transcriptional Enhanced Associated Domain) is a family of transcription factors whose involvement in the Hippo pathway plays a crucial role in cellular homeostasis and preventing tumorigenesis. Aberrant YAP/TAZ-TEAD activation is a key driver of various cancers, making it an attractive and therapeutically relevant target. Current challenges include nephrotoxicity as a potential on-target effect and acquired resistance, issues which are prompting the design of intermittent dosing schedules and the use of combination therapies. This review aims to provide a comprehensive overview of the current literature and patent landscape of TEAD inhibition, critically examining their mechanisms of action, preclinical and clinical efficacy, and therapeutic benefits. Covalent, non-covalent TEAD palmitate pocket binders, PPIDs and PROTACs are reviewed in part I, while part II will focus on their applications in mono- and combination therapies. The global patent database WIPO (World Intellectual Property Organization) as well as the chemical database SciFinder© were queried using the keywords "TEAD inhibitor", manually classified into PPID and non-PPID drugs and further subdivided into covalent and non-covalent inhibitors, resulting in 123 patents from March 2017 to December 2024 (excluding peptidomimetics and biologics).