9ogi | pdb_00009ogi
Structure of TEAD2 bound to G8025
Structural highlights
FunctionTEAD2_HUMAN Transcription factor which plays a key role in the Hippo signaling pathway, a pathway involved in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein MST1/MST2, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Acts by mediating gene expression of YAP1 and WWTR1/TAZ, thereby regulating cell proliferation, migration and epithelial mesenchymal transition (EMT) induction. Binds to the SPH and GT-IIC 'enhansons' (5'-GTGGAATGT-3'). May be involved in the gene regulation of neural development. Binds to the M-CAT motif.[1] [2] Publication Abstract from PubMedTEAD 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(G12C) 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. Covalent pan-TEAD inhibitors block YAP activity and demonstrate brain penetrance in a Hippo-dependent cancer model.,Hagenbeek TJ, Zbieg J, Smith R, Paul S, Gerosa L, Torrini C, Guarnaccia AD, Ong C, Lacap JA, Ning M, Sodir NM, Hafner M, Tremblay J, Hawley J, Chan B, Verma VA, Beveridge RE, Hsu PL, 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 SA, Shanahan F, Fong R, Boenig G, Di Lello P, Kubala MH, Hunsaker T, Ravichandran M, Saenz-Lopez Larrocha P, Lau J, An L, Levy E, Lorenzo MN, Lill JR, Modrusan ZD, Chen YC, Yao X, Brastianos PK, Maddalo D, Dey A Nat Commun. 2026 Jun 27. doi: 10.1038/s41467-026-74722-5. PMID:42365001[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
