Yap1, also known as Yap, is a protein that acts as a transcription regulator by activating the transcription of genes involved in cell proliferation and inhibiting apoptosis. Specifically, Yap1 is inhibited in the hippopotamus signaling pathway, which can control organ size and inhibit tumors. Besides, hippopotamus signaling regulates Yap1 binding and CO activation of transcription factors in the tea domain (tead). Moreover, Yap1 combines with tead4 through a large flat interface, and Yap1 promotes tumor progression and metastasis through tead interaction. Cyclic Yap like peptide and recombinant protein (such as VGLL) can destroy the in vitro interaction between tead and Yap1. Furthermore, VGLL, directly competing for Yap1 as a common binding site on tead, negatively regulates the activity of tead / yap and inhibits the activity of lung and stomach tumors. TED-347 is a potent, irreversible, covalent and allosteric inhibitor at YAP-TEAD protein-protein interaction
TED-347 is a potent, irreversible, covalent, and allosteric inhibitor at YAP-TEAD protein-protein interaction.
But, how does TED-347 protect against cancer cells via YAP-TEAD protein-protein interaction? Let’s discuss it in detail. First of all, TED-347 has an EC50 of 5.9 μM for TEAD4⋅Yap1 protein-protein interaction. In addition, TED-347 specifically and covalently bonds with Cys-367 within the central pocket of TEAD4 with a Ki of 10.3 μM. TED-347 blocks TEAD transcriptional activity and has antitumor activity.
In the second place, TED-347 inhibits GBM43 cancer cell viability and inhibits co-immunoprecipitation of Myc-tagged TEAD4 with FLAG-tagged Yap1. Meanwhile, TED-347 shows a significant reduction in CTGF transcript levels. Nonetheless, TED-347 reduces reporter activity in cells transfected with a TEAD reporter and inhibits TEAD4 transcriptional activity in GBM43 cells. Additionally, TED-347 inhibits TEAD4 binding to full-length Yap1 in a dose- and time-dependent manner. Importantly, TED-347 shows no inhibition of uPAR•uPA or Cav2.2 α•β protein-protein interactions. Particularly, TED-347 has the maximum rate of inactivation of 0.038 hours, corresponding to a t1/2∞ of 18.2 hours.
All in all, TED-347 is a potent, irreversible, covalent, and allosteric inhibitor at YAP-TEAD protein-protein interaction with antitumor activity.
References:
Khuchtumur Bum-Erdene, et al. Cell Chem Biol. 2019 Mar 21;26(3):378-389.e13.