Covalent pan-TEAD inhibitors block YAP activity and demonstrate brain penetrance in a Hippo-dependent cancer model
Year: 2026
Type: article
Abstract: TEAD transcription factors enable the oncogenic activity of deregulated Hippo signaling and are a promising therapeutic target in oncology. Targeting the TEAD lipid pocket is an established path to inhibit the oncogenic activities of cofactors YAP and TAZ. Here we present two pan-TEAD inhibitors, GNE-8025 and its in vivo brain-penetrant derivative GNE-2181, that covalently bind the lipid pocket at a conserved cysteine. Both small molecules show growth inhibition of YAP-driven tumor cells in vitro and in vivo. Moreover, we show that GNE-8025 increases the activity of a broad range of MAPK pathway inhibitors in vitro as well as the KRASG12C inhibitor Divarasib both in vitro and in vivo. In addition, GNE-2181 inhibits growth of an intracranial tumor model in vivo. Altogether we present a next-generation class of TEAD inhibitors representing a significant advancement towards potent, specific, and effective Hippo-targeting cancer therapies. Hyperactive YAP/TAZ-TEAD signaling is a common mechanism of resistance to targeted therapies. Here, the authors discover that covalent pan-TEAD inhibitors, including a brain-penetrant inhibitor, decrease YAP activity and suppress both peripheral and intracranial tumor growth.
Source: Nature Communications
Authors: Thijs J. Hagenbeek, Jason Zbieg, Russell Smith, Sayantanee Paul, Luca Gerosa, Consuelo Torrini, Alissa D. Guarnaccia, Christy Ong, Jennifer A. Lacap, Miaoran Ning, Nicole M. Sodir, Marc Hafner, Julien Tremblay, James Hawley, Bryan Chan, Vishal A. Verma, Ramsay E. Beveridge, Peter L. Hsu, Gözde Ulas, Lisha Wang, Jim Nonomiya, Shu Chen, Victoria Pham, Joshua Webster, Jessica Preston, Jeff Hung, Jeff Eastham, Debra Dunlap, Wendy Lee, Paul Beroza, Naema Nayyar, Scott Martin, Eva Lin, Julie Weng, Scott A. Foster, Frances Shanahan, Rina Fong, Gladys Boenig, Paola Di Lello, Marta H. Kubala, Thomas Hunsaker, Mirunalini Ravichandran, Pablo Saenz-Lopez Larrocha, Jeffrey Lau, Le An, Elizabeth Levy, Maria N. Lorenzo, Jennie R. Lill, Zora D. Modrusan, Yi-Chen Chen, Xiaosai Yao, Priscilla K. Brastianos, Danilo Maddalo, Anwesha Dey
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G1229526393, G1286251239, G2371548206, G262532246, G303061748, G315621713, G4202012489, G4235786860, G4581610328, G495301720, G498139845, G5570207115, G6550344761, G7283024673, G7396808078, G7863156295, G8207748872, G8382000481, G8925327636, A Synchrotron Radiation Structural Biology Resource, G911061179, G969889393, Mass General Brigham Training Program in Precision and Genomic Medicine
OpenAlex ID: W7166327128