Targeting TEAD1-4, a set of nuclear transcription factors that are key effectors of the Hippo pathway, have become of increased recent interest in part due to the potential for TEAD inhibitors and degraders to synergize with RAS inhibition. GNE-7883 is an allosteric, pan-TEAD tool compound from Genentech used to demonstrate in vivo proof-of-concept for combination therapy between a TEAD inhibitor and a KRAS(G12C) inhibitor. The molecule is notable as an example of a reversible molecule targeting all four paralogs of a traditionally difficult-to-drug transcription factor. This article highlights the rational design of an allosteric pan-TEAD inhibitor from a FRET-based HTS, and the activities of GNE-7883 in YAP/TAZ-dependent cancers, and highlights the potential applications of TEAD inhibitors in precision oncology.
6 minute read
Nov. 16, 2023
GNE-7883: Proof-of-Concept for TEAD and RAS Inhibitor Synergy
pan-TEAD inhibitor preclinical efficacy in xenograft models from TEAD3-YAP HTS of >2M cmpds + opt. Nature, June 5, 2023 Genentech, South San Francisco, CA