GNE-7883

Through careful biophysical characterization, GNE-7883 was shown to interact specifically with TEAD at its lipid binding site, allosterically preventing interactions at a specific protein-protein interface with YAP/TAZ in TR-FRET assays at low nanomolar concentrations. GNE-7883 also showed selective cellular growth inhibition in the YAP/TAZ-dependent cell lines OVCAR-8 and HCC1576, but not a YAP/TAZ independent cell line SK-N-FI. An X-Ray co-crystal structure that was solved for compound GNE-7883 bound to TEAD, along with that of a structurally related but less potent compound shows engagement in the lipid-binding pocket and is consistent with its biophysical activity. Finally, a structurally related negative control compound is described that is inactive in the TR-FRET biophysical assay and does not inhibit cell growth of YAP/TAZ-dependent cell lines. This collection of data provides good confidence that the cellular activities of GNE-7883 are a specific result of TEAD target engagement and that GNE-7883 has strong utility as a probe to interrogate the biology of disrupting YAP/TAZ and TEAD. Limitations of this probe are that there is no disclosed data on its activity against targets outside of the TEAD family (e.g. kinases, GPCRs, etc.) so potential off-target activities are unknown. Moreover, because it is a pan TEAD inhibitor, it is not useful to distinguish TEAD subtype biology. Finally, the GNE-7883 is not orally available and must be administered IP or subcutaneously in chronic studies.