pan-TEAD inhibitor ISM6331

An orally bioavailable non-covalent small molecule inhibitor of the TEA domain (TEAD) family of transcription factors, including TEAD1, TEAD2, TEAD3 and TEAD4, with potential antineoplastic activity. Upon oral administration, pan-TEAD inhibitor ISM6331 reversibly binds to the TEAD palmitoylation site and inhibits TEAD, thereby disrupting the interaction between the transcription co-activators yes-associated protein 1 (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) and TEAD. 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. It plays a key role in cancer initiation, progression, and cancer cell resistance to various therapies.