9OGI

Structure of TEAD2 bound to G8025

This is a non-PDB format compatible entry.

Summary for 9OGI

• Entry DOI: 10.2210/pdb9ogi/pdb
• Descriptor: Transcriptional enhancer factor TEF-4, N-({4-[(1S)-1,2-dihydroxyethyl]-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}methyl)propanamide (3 entities in total)
• Functional Keywords: inhibitor, transcription, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 57878.99

Authors

Hsu, P.L.,Boenig, G. (deposition date: 2025-04-30, release date: 2026-07-08)

Primary citation

Hagenbeek, T.J.,Zbieg, J.,Smith, R.,Paul, S.,Gerosa, L.,Torrini, C.,Guarnaccia, A.D.,Ong, C.,Lacap, J.A.,Ning, M.,Sodir, N.M.,Hafner, M.,Tremblay, J.,Hawley, J.,Chan, B.,Verma, V.A.,Beveridge, R.E.,Hsu, P.L.,Ulas, G.,Wang, L.,Nonomiya, J.,Chen, S.,Pham, V.,Webster, J.,Preston, J.,Hung, J.,Eastham, J.,Dunlap, D.,Lee, W.,Beroza, P.,Nayyar, N.,Martin, S.,Lin, E.,Weng, J.,Foster, S.A.,Shanahan, F.,Fong, R.,Boenig, G.,Di Lello, P.,Kubala, M.H.,Hunsaker, T.,Ravichandran, M.,Saenz-Lopez Larrocha, P.,Lau, J.,An, L.,Levy, E.,Lorenzo, M.N.,Lill, J.R.,Modrusan, Z.D.,Chen, Y.C.,Yao, X.,Brastianos, P.K.,Maddalo, D.,Dey, A.
Covalent pan-TEAD inhibitors block YAP activity and demonstrate brain penetrance in a Hippo-dependent cancer model.
Nat Commun, 2026

PubMed 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 KRAS 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.

PubMed: 42365001
DOI: 10.1038/s41467-026-74722-5

Experimental method

X-RAY DIFFRACTION (2.25 Å)