VT-107 is a Pan-TEAD Auto-Palmitoylation Inhibitor
Posted On 2021-08-18
TEA domain (TEAD) transcription factors are sequence-specific DNA binding proteins that regulate transcription. TEAD family transcription factors all contain a DNA-binding domain called a TEA domain. In mammals, TEAD consists of four members (TEAD1-TEAD4), and they share high degree of sequence homology and highly similar structural domain architectures. Besides, TEAD widely exists in preimplantation embryos to various adult tissues, with distinct patterns. What’s more, TEAD proteins regulate development of various tissues, including heart, skeletal muscles, neural crest, notochord and trophoectoderm.
Mammalian TEAD proteins regulate cell proliferation and contact inhibition as transcriptional mediators of Hippo signaling. The Hippo pathway plays an essential role in controlling organ size and maintaining tissue homeostasis. Downstream from the Hippo kinase core are the co-factors YAP and TAZ transcriptional co-activators. Importantly, when the Hippo kinase core is inactivated, YAP and TAZ become dephosphorylated and translocate into the nucleus, where they interact predominantly with the TEAD transcription factors, resulting in the activation of transcriptional programs important for cell proliferation, survival, and migration. According to reports, Hippo-YAP pathway is dysregulated frequently in malignant mesothelioma and in other YAP-driven cancers and diseases. Therefore, small molecules that block TEAD function have been the subject of considerable research.
VT-107 is a potent and pan-TEAD auto-palmitoylation inhibitor.
VT-107 exhibits broad-spectrum TEAD inhibition. And it can block palmitoylation of all four TEAD proteins. By the way, VT-107 inhibits TEAD auto-palmitoylation by blocking the palmitoyl-CoA binding site. Specifically, VT-107 results in the disappearance of palmitoylated TEAD1 with a concomitant increase in unpalmitoylated TEAD1. Meanwhile, VT107 can decrease the levels of palmitoylated TEAD3 and TEAD4 and increase the levels of unpalmitoylated TEAD3 and TEAD4. Therefore, VT107 inhibits the proliferation of NF2-deficient mesothelioma cells. VT107 exhibits anti-tumor activity.
In conclusion, VT-107 is a potent and pan-TEAD auto-palmitoylation inhibitor. VT-107 can inhibit the proliferation of NF2-deficient mesothelioma cells.
Sawada A, et, al. Development. 2005 Nov;132(21):4719-29.