Journal article
An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance
TJ Hagenbeek, JR Zbieg, M Hafner, R Mroue, JA Lacap, NM Sodir, CL Noland, S Afghani, A Kishore, KP Bhat, X Yao, S Schmidt, S Clausen, M Steffek, W Lee, P Beroza, S Martin, E Lin, R Fong, P Di Lello Show all
Nature Cancer | Published : 2023
Open access
Abstract
The Hippo pathway is a key growth control pathway that is conserved across species. The downstream effectors of the Hippo pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), are frequently activated in cancers to drive proliferation and survival. Based on the premise that sustained interactions between YAP/TAZ and TEADs (transcriptional enhanced associate domain) are central to their transcriptional activities, we discovered a potent small-molecule inhibitor (SMI), GNE-7883, that allosterically blocks the interactions between YAP/TAZ and all human TEAD paralogs through binding to the TEAD lipid pocket. GNE-7883 effectively reduces chromatin acc..
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