GNE-2181 is a potent, selective, covalent, orally bioavailable and brain-penetrant pan-TEAD inhibitor, disrupts YAP-TEAD interaction with biochemical IC50s of 2/4/8/6 nM for TEAD1/2/3/4 in TR-FRET assays.
GNE-2181 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-2181 exhibits strong activity against all four isoforms of TEAD.
GNE-2181 potently inhibits cell proliferation of Hippo-driven cell lines NCI-H226 and MSTO-211H with EC50 of 3 nM and 7 nM, but not Hippo-independent VMRC-LCD cells with >2500-fold higher EC50 values.
GNE-2181 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-2181 enhances the efficacy of targeted cancer therapies, particularly when combined with inhibitors of RTKs and the RAS/MAPK pathway.
GNE-2181 (10 or 50 mg/kg) effectively inhibited brain tumor growth in brain metastasis with advanced stage lung cancer NCI-H226, with a concomitant reduction of the YAP/TAZ target score and proliferation marker (Ki67).