Extended Data Fig. 1: Discovery of small molecule inhibitors blocking TEAD interaction with YAP/TAZ.
(a) Chemical structures and key biochemical and cellular activity data for Compounds 2, 3, and 4. (b) Crystal structure of Compound 2 bound in the TEAD2 lipid pocket. Site 2 is shown for reference. Compound is shown in green stick representation. (c) Overlay of Sites 2 and 3 for the structures of GNE-7883 bound to TEAD2 (blue) and a non-allosteric lipid pocket compound bound to TEAD2 (PDB 6UYC, grey). The YAP Site 2 helix or Site 3 omega loop from PDB 3KYS is overlaid in transparent purple for reference. (d) (Left) 19F NMR spectrum of fluorinated peptides S2 and S3 at and (Middle) in the presence of TEAD2. The 19F NMR signals for the free S2 and S3 peptides are reduced upon binding to TEAD2. (Right) Overlay of the 19F NMR spectra of S2 and S3 in the presence of TEAD2 (black trace) and after addition of Compound 2 (red trace). (e) (Left) 19F NMR spectrum of fluorinated peptides S2 and S3 at 20 μM. (Middle) 19F NMR spectrum of peptides S2 and S3 at 20 μM in the presence of 10 μM TEAD. (Right) 19F NMR spectrum of peptide S2 and S3 at 20 μM in the presence of 10 μM TEAD2-YAP and 55 μM pepYAP.
