VT00278

VT00278 is a small molecule inhibitor of the TEA domain (TEAD) transcription factors, which are the primary nuclear effectors of the Hippo signaling pathway. Described as a chemical analog of CA3, VT00278 disrupts the interaction between YAP1 and TEAD, thereby downregulating the transcriptional activity of genes involved in tumor progression, metastasis, and therapy resistance. In preclinical models of gastroesophageal adenocarcinoma (GEAC) and gastric cancer with peritoneal metastases (GCPM), VT00278 has demonstrated the ability to suppress tumor cell proliferation, invasion, and sphere formation while inducing apoptosis. Mechanistically, it also impairs RNA polymerase II activity, reduces the expression of the anti-apoptotic protein MCL-1, and activates the cytosolic DNA sensing pathway, leading to the induction of innate immune genes such as IFNβ and the upregulation of PD-L1. These effects contribute to the remodeling of the immunosuppressive metastatic niche and enhance the response to immune checkpoint inhibitors like anti-PD-1.