Discovery and characterization of sulfonamide derivatives as transcriptional enhanced associate domain (TEAD) inhibitors: a novel approach for targeting hepatocellular carcinoma.

Transcriptional enhanced associate domain (TEAD), overexpressed in hepatocellular carcinoma (HCC) and inversely correlated to prognosis, has emerged as a promising target for HCC therapy. To date, no small-molecule inhibitors targeting TEAD have been reported for HCC treatment. In this study, a bioinformatic analysis has been performed and has demonstrated that TEAD is a promising target for therapeutic intervention in HCC. Then, a series of sulfonamide derivatives, discovered by virtual screening and structure optimization, were rigorously evaluated for their anti-proliferative effects across various HCC cell lines. Among these, compound C11 demonstrated exceptional efficacy in inhibiting HCC cell viability and exhibited favorable pharmacokinetic properties. Mechanistic studies revealed that C11 acts as a novel TEAD modulator, selectively downregulating TEAD-dependent downstream genes. These findings underscore C11's potential as a therapeutic agent and establish a new paradigm in TEAD-targeted strategies for HCC treatment.