Fig. 1: Discovery and characterization of the potent pan-TEAD inhibitor GNE-7883.
a, Chemical structures and key biochemical and cellular activity data for compound 1 and GNE-7883. b, Crystal structure of compound 1 (top row) and GNE-7883 (bottom row) bound in the TEAD2 lipid pocket. Site 2 is shown for reference. The compounds are shown in green stick representation. c, Overlay of the crystal structures of GNE-7883 bound to TEAD2 and a compound known to bind in the lipid pocket but not inhibit YAP/TAZ binding (Protein Data Bank accession 6UYC, colored gray). d, Left, 19F NMR spectrum of fluorinated peptides S2 and S3 at 20 μM. Middle, 19F NMR spectrum of fluorinated peptides S2 and S3 at 20 μM in the presence of 10 μM TEAD2. The 19F NMR signals for the free S2 and S3 peptides are reduced upon binding to TEAD2. Right, overlay between the 19F NMR spectra of 20 μM S2 and S3 in the presence of 10 μM TEAD2 (black trace) and after the addition of 55 μM GNE-7883 (red trace). e, Dose–response curve showing displacement of the site 2 probe by GNE-7883, confirming allosteric perturbation of TEAD2 site 2. Under the same assay conditions, YAP 50–100 displacement plateaus at 60%, while no perturbation of the site 3 probe is observed with GNE-7883. The experiment was performed once with two technical replicates. f, Nuclear and cytosolic fractionation (left) of YAP-amplified OVCAR-8 cells treated with 3 μM TEAD SMI or dimethyl sulfoxide (DMSO). In parallel, reciprocal immunoblotting of YAP and TAZ was conducted following immunoprecipitation with a pan-TEAD antibody (right). The experiments were repeated twice with consistent results.
