2026/06/27 by Thijs J. Hagenbeek, Jason Zbieg, Russell Smith +51 · 1 voice
Biochemistry, Genetics and Molecular Biology · Neuroscience · #Axon Guidance and Neuronal Signaling #Cancer #Hedgehog signaling pathway #Hippo pathway signaling and YAP/TAZ #Hippo signaling pathway #In vitro #In vivo #Signal transduction #Small molecule #Transcription (linguistics) #Transcription factor #Wnt/β-catenin signaling in development and cancer
paper · doi:10.1038/s41467-026-74722-5
openalex publication_date 2026/06/27 · openalex created_date 2026/06/28 · openalex updated_date 2026/08/06
TEAD transcription factors enable the oncogenic activity of deregulated Hippo signaling and are a promising therapeutic target in oncology. Targeting the TEAD lipid pocket is an established path to inhibit the oncogenic activities of cofactors YAP and TAZ. Here we present two pan-TEAD inhibitors, GNE-8025 and its in vivo brain-penetrant derivative GNE-2181, that covalently bind the lipid pocket at a conserved cysteine. Both small molecules show growth inhibition of YAP-driven tumor cells in vitro and in vivo. Moreover, we show that GNE-8025 increases the activity of a broad range of MAPK pathway inhibitors in vitro as well as the KRASG12C inhibitor Divarasib both in vitro and in vivo. In addition, GNE-2181 inhibits growth of an intracranial tumor model in vivo. Altogether we present a next-generation class of TEAD inhibitors representing a significant advancement towards potent, specific, and effective Hippo-targeting cancer therapies. Hyperactive YAP/TAZ-TEAD signaling is a common mechanism of resistance to targeted therapies. Here, the authors discover that covalent pan-TEAD inhibitors, including a brain-penetrant inhibitor, decrease YAP activity and suppress both peripheral and intracranial tumor growth.