8P0M

Crystal structure of TEAD3 in complex with IAG933

Summary for 8P0M

• Entry DOI: 10.2210/pdb8p0m/pdb
• Descriptor: Transcriptional enhancer factor TEF-5, 2-(2-{2-[2-(2-METHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHANOL, MYRISTIC ACID, ... (7 entities in total)
• Functional Keywords: inhibitor, complex, transcription
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 105243.84

Authors

Scheufler, C.,Villard, F.,Chau, S. (deposition date: 2023-05-10, release date: 2024-04-10, Last modification date: 2024-08-07)

Primary citation

Chapeau, E.A.,Sansregret, L.,Galli, G.G.,Chene, P.,Wartmann, M.,Mourikis, T.P.,Jaaks, P.,Baltschukat, S.,Barbosa, I.A.M.,Bauer, D.,Brachmann, S.M.,Delaunay, C.,Estadieu, C.,Faris, J.E.,Furet, P.,Harlfinger, S.,Hueber, A.,Jimenez Nunez, E.,Kodack, D.P.,Mandon, E.,Martin, T.,Mesrouze, Y.,Romanet, V.,Scheufler, C.,Sellner, H.,Stamm, C.,Sterker, D.,Tordella, L.,Hofmann, F.,Soldermann, N.,Schmelzle, T.
Direct and selective pharmacological disruption of the YAP-TEAD interface by IAG933 inhibits Hippo-dependent and RAS-MAPK-altered cancers.
Nat Cancer, 5:1102-1120, 2024

PubMed Abstract: The YAP-TEAD protein-protein interaction mediates YAP oncogenic functions downstream of the Hippo pathway. To date, available YAP-TEAD pharmacologic agents bind into the lipid pocket of TEAD, targeting the interaction indirectly via allosteric changes. However, the consequences of a direct pharmacological disruption of the interface between YAP and TEADs remain largely unexplored. Here, we present IAG933 and its analogs as potent first-in-class and selective disruptors of the YAP-TEAD protein-protein interaction with suitable properties to enter clinical trials. Pharmacologic abrogation of the interaction with all four TEAD paralogs resulted in YAP eviction from chromatin and reduced Hippo-mediated transcription and induction of cell death. In vivo, deep tumor regression was observed in Hippo-driven mesothelioma xenografts at tolerated doses in animal models as well as in Hippo-altered cancer models outside mesothelioma. Importantly this also extended to larger tumor indications, such as lung, pancreatic and colorectal cancer, in combination with RTK, KRAS-mutant selective and MAPK inhibitors, leading to more efficacious and durable responses. Clinical evaluation of IAG933 is underway.

PubMed: 38565920
DOI: 10.1038/s43018-024-00754-9

Experimental method

X-RAY DIFFRACTION (1.961 Å)