The Hippo signaling pathway is involved in normal cell growth and homeostasis, and when dysregulated, implicated in various cancers. Transcriptional co-regulators YAP/TAZ act downstream of Hippo signaling. When Hippo pathway is not active, YAP/TAZ are hypo-phosphorylated and translocated into the nucleus to bind to TEAD family of transcription factors, activating gene transcription program responsible for proliferation and repair of cells, tissues and organs. Therefore, YAP/TAZ-TEAD complex plays a central role in the execution of cell fate regulated by Hippo signaling. Interestingly, the C-terminal domain of TEAD that binds to YAP/TAZ has a hydrophobic core that houses an endogenous palmitate via a conserved cysteine residue. The absence of endogenous palmitate was shown to disrupt YAP-TEAD binding and transcriptional activity. We postulated that the hydrophobic core of TEAD could potentially be up- or down-regulated by Hippo signaling activities. In our lab, we demonstrated the ability of modulating TEAD transcriptional activity by leveraging on the hydrophobic core. We discovered that flufenamic acid could occupy the hydrophobic core of TEAD, and inhibit YAP/TAZ-TEAD transcriptional activities. Thus, blocking the palmitoylation site may be a potential therapeutic strategy for cancers with hyper-activated YAP/TAZ-TEAD activities. On the other hand, we reported that quinolinol class of compounds could also occupy the hydrophobic core of TEAD, and activate/up-regulate cells’ basal YAP/TAZ-TEAD transcriptional activities. Furthermore, quinolinol class of compounds accelerated wound closure in a mouse wound-healing model, highlighting the potential of targeting TEAD in the context of regenerative medicine in addition to cancer therapy.

Targeting the hydrophobic pockets of TEADs for potential cancer therapy or regenerative medicine

ACS Spring Meeting 2021

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