The Hippo pathway, and specifically the YAP/TAZ–TEAD transcriptional complex, has been shown to be a promising target for the treatment of cancer. Intrigued by the potential of disrupting the YAP/TAZ–TEAD transcriptional complex an HTS screen against TEAD3–YAP was initiated and a novel core was identified as a micromolar inhibitor of TEAD3–YAP. It was discovered that these ligands bind an allosteric pocket on TEAD which disrupts the binding of YAP/TAZ. Rational structure-based design of the HTS hit overcame TEAD4 potency challenges to produce GNE-7883. GNE-7883 has pan-TEAD binding across TEADs 1-4 which correlates to potency against YAP/TAZ binding for TEADs 1-4. Good physiochemical and ADME properties of this tool compound allows for clear demonstration of on-target antiproliferative effects in vitro and Hippo pathway target gene modulation in vivo.

Discovery of GNE-7883, a novel reversible pan-TEAD binder which functions as an allosteric inhibitor against YAP/TAZ: Hit identification, rational design and in Vivo PK/PD results

ACS Spring Meeting 2021

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