Investigation of the transcription factor TEAD-based material basis of Astragalus synergistic dacarbazine in the treatment of uveal melanoma

Abstract Uveal melanoma (UM) is the most common intraocular malignancy in adults, and despite great advances in combination drug therapies based on UM-related pathways, targeted therapies remain an unmet medical need, and there has been a decrease in sensitivity to chemotherapy. Astragalus, as a medicinal and edible herbs, may play a role in the treatment of cancer by combining different chemotherapeutic agents. In this study, we first found that Astragalus can be combined with dacarbazine for the treatment of uveal melanoma using a hormonal mouse model and determined that the transcription factor TEAD may be one of the reasons for the reduced sensitivity of uveal melanoma to dacarbazine chemotherapy. Subsequently, using a multidisciplinary approach of computer-aided drug design combined with cellular experiments and molecular pairing, we found that RISO, a compound in Astragalus, stabilised the binding of YAP/TEAD, reduced the expression of the downstream pathway proteins CCN1, CTGF and CARP, promoted the reduction of mitochondrial membrane potential in 92.1 cells, and induced apoptosis and cell cycle arrest in 92.1 cells, which had a synergistic effect with dacarbazine. Moreover, the integration of molecular dynamics simulations with energy analysis identified (R)-isomontanol as a promising inhibitor. The identification of key hydrophobic residues is of paramount importance, as these residues have been shown to be crucial for TEAD-ligand interactions. Furthermore, these residues have been demonstrated to exhibit both high binding stability and the strongest pharmacological potential when compared to the other investigated compounds. This provides valuable insights for the design of more potent TEAD inhibitors in future studies. These findings provide new ideas and drugs for the treatment of UM. Bridging the gap in research on the interaction of Astragalus with transcription factors.