Comparative Analysis of TEAD Inhibitor Efficacy in Hepatocellular Carcinoma Cells

Hepatocellular carcinomas (HCC) are a major health concern, surpassing already today half a million deaths each year. HCCs are prone to rapidly develop resistance against common anti-cancer drugs, thereby strongly limiting suitable treatment regimens and therefore warranting the need for novel drugs. Transcriptional enhancer factor TEF (TEAD) inhibitors are a promising class of inhibitors that target the interaction between TEAD transcription factors and their co-factors yes-associated protein (YAP) and WW Domain Containing Transcription Regulator 1 (WWTR1; TAZ). YAP/TAZ are effectors of the Hippo pathway, which regulates cell proliferation and organ growth, and is abnormally activated in 60% of all HCC patients. This hyperactivation is associated with fast tumor progression and poor patient outcomes. Many different TEAD inhibitors are currently under development with the most advanced ones already in clinical trials. We evaluated eight TEAD inhibitors (seven of them kindly provided by Merck Healthcare KGaA) in the HCC cell line HLF. The effects of these molecules on the interaction between YAP/TAZ and TEAD1 or TEAD4, were studied using CoIP, proximity ligation and NanoBiT assays. We determined IC50 values as well as time-resolved interaction dynamics. Additionally, we evaluated the effects of the drugs on a TEAD-luciferase-reporter system, cell viability, as well as on selected target genes, using quantitative PCR (qPCR). Publication History Article published online: 26 January 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany