GNE-8025 is a potent, selective, covalent pan-TEAD inhibitor, disrupts YAP-TEAD interaction with biochemical IC50s of 5/8/326/37 nM for TEAD1/2/3/4 in TR-FRET assays.
GNE-8025 bind potently and covalently to the lipid pocket of TEAD proteins, form a covalent linkage with the lipid pocket cysteine (C380) of TEAD2 through the acrylamide warhead.
GNE-8025 exhibits strong activity against all four isoforms of TEAD1/2/4, with the exception of TEAD3.
GNE-8025 potently inhibits cell proliferation of Hippo-driven cell lines NCI-H226 and MSTO-211H with EC50 of 7 nM and 22 nM, but not Hippo-independent VMRC-LCD cells with >2500-fold higher EC50 values.
GNE-8025 shows superior efficacy in both NCI-H226 and MSTO-211H cells versus GNE-6915 and GNE-7883, downregulates YAP/TAZ–TEAD-dependent gene programs to exert anti-proliferative effects.
GNE-8025 potently inhibits the proliferation of Hippo deregulated cells and reinforces mesothelioma as a malignancy where TEAD inhibitors are effective at impeding cancer cell proliferation.
GNE-8025 enhances the efficacy of targeted cancer therapies, particularly when combined with inhibitors of RTKs and the RAS/MAPK pathway.
GNE-8025 (10 mg/kg BID) significantly impacted tumor growth inhibition in NCI-H226 xenograft model.