I-Ju Yeh, Khuchtumur Bum-Erdene, Mona K. Ghozayel, Giovanni Gonzalez-Gutierrez, and Samy O. Meroueh
ACS Chemical Biology 2025
https://pubs.acs.org/doi/10.1021/acschembio.5c00283
Transcriptional enhanced associate domain transcription factors (TEAD1 to TEAD4) bind to transcriptional coactivator Yes-Associated Protein (YAP1) or its paralog transcriptional coactivator with PDZ-binding motif (TAZ) to regulate Hippo pathway target genes. The Hippo pathway is a conserved signaling pathway that regulates organ size and cell fate by controlling cell proliferation and apoptosis. Here we report small acrylamide molecules that form a covalent bond with a conserved cysteine at the TEAD palmitate pocket. Binding studies showed profound stabilization of TEADs by the small molecules, and cocrystal structures reveal that the compounds mimic the binding mode of palmitate. The small molecules achieved submicromolar binding constants and subhour reaction half-lives for all four TEADs. In mammalian cells, the compounds stabilize the TEAD•YAP1 interaction yet inhibit the TEAD transcription factor activity. Unexpectedly, several compounds degraded TEAD and YAP1 proteins and inhibited cancer cell viability. This work suggests that degradation of TEAD and YAP1 may amplify the antitumor effects of small molecules targeting the TEAD palmitate pocket, with implications for other cancer targets featuring allosteric lipid-binding sites.
