Covalent pan-TEAD inhibitors block YAP activity and demonstrate brain penetrance in Hippo-dependent cancer models [Quant-seq]

Targeting the lipid pocket of TEAD is an established path to inhibit the oncogenic activities of the cofactors YAP and TAZ. Here we present two covalent pan-TEAD inhibitors that bind to the lipid pocket, GNE-8025 and GNE-2181.

GNE-8025 binds TEAD proteins covalently at a conserved cysteine residue to engage the lipid pocket and allosterically disrupt the interaction of TEAD proteins with YAP. GNE-2181 is a further optimized version of GNE-8025 with properties that enable brain penetrance in vivo. Both of these small molecules suppress the proliferation of YAP-driven tumor cells both in vitro and in vivo and increase activity of a broad range of inhibitors of the MAPK pathway.