Definition

An orally bioavailable, small molecule inhibitor of the transcription factor TEAD (TEA domain), with potential antineoplastic activity. Upon oral administration, TEAD inhibitor BPI-460372 targets and covalently binds to the cysteine residue in the TEAD palmitoylation pocket, thereby disrupting the interaction between the transcription co-activators yes-associated protein 1 (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) and TEAD and irreversibly inhibiting TEAD auto-palmitoylation. This may inhibit YAP/TAZ-TEAD-promoted transcription of multiple genes involved in tumor cell proliferation, progression and survival, and may result in enhanced apoptosis in TEAD-dependent cancers. Hippo pathway alterations, as seen in tumors with neurofibromatosis type 2 (NF2)-deficiency, large tumor suppressor 1 (LATS1) and 2 (LATS2) mutations and YAP/TAZ fusions, lead to Hippo pathway activation, hyperactivation of YAP/TAZ and activation of TEAD.