Towards the design of ligands of the internal pocket TEADs C-terminal domain

The Hippo pathway controls in organ size and tissue homeostasis through regulating cell growth, proliferation and apoptosis. Phosphorylation of the transcription co-activator YAP (Yes associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif) regulates their nuclear import and therefore their interaction with TEAD (Transcriptional Enhanced Associated Domain). YAP, TAZ and TEADs are dysregulated in several solid cancers making YAP/TAZ-TEAD interaction a new anti-cancer target. We identified by screening a small in-house library, 5-benzyloxindole which binds to hTEAD2 at its internal/palmitate pocket. Its optimization led to covalent inhibitors bearing different warhead. Soaking with hTEAD2 gave seven new crystal structures where the ligands occupied palmitate pocket. 5-Benzyloxyindoles armed with vinylsulfamide moiety inhibit YAP/TAZ-TEAD target genes expression and breast cancer cell proliferation at micromolar concentration. [Display omitted] •Characterization and optimization of covalent and non-covalent ligands of the internal pocket of TEAD.•Best compounds alter the expression of YAP/TAZ-TEAD target genes - CTGF, Cyr61, AXL and BIRC5.•Best compounds inhibit cell proliferation of breast cancer cells.