An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance
The Hippo pathway is a critical growth control mechanism that is conserved across species. In many cancers, the downstream effectors of this pathway—YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif)—are often activated, driving tumor cell proliferation and survival. Recognizing that persistent interactions between YAP/TAZ and TEADs (transcriptional enhanced associate domain) are essential for their transcriptional activities, we identified a potent small-molecule inhibitor (SMI), GNE-7883, which allosterically disrupts the binding between YAP/TAZ and all human TEAD paralogs by targeting the TEAD lipid pocket.
GNE-7883 effectively reduces chromatin accessibility at TEAD-binding motifs, suppresses cell proliferation across various cell line models, and demonstrates strong antitumor activity in vivo. Furthermore, our study revealed that GNE-7883 can overcome both intrinsic and acquired resistance to KRAS G12C inhibitors in preclinical models, primarily by inhibiting YAP/TAZ activation.
In summary, our findings highlight the potential of TEAD small-molecule inhibitors in YAP/TAZ-dependent cancers and their broad applicability in precision oncology,HC-258 including overcoming therapy resistance.