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DOI 10.1038/s41467-026-74722-5

Медицинская библиотека · Nature communications · 2026

Covalent pan-TEAD inhibitors block YAP activity and demonstrate brain penetrance in a Hippo-dependent cancer model.

Hagenbeek Thijs J, Zbieg Jason, Smith Russell, Paul Sayantanee, Gerosa Luca, Torrini Consuelo, Guarnaccia Alissa D, Ong Christy, Lacap Jennifer A, Ning Miaoran, Sodir Nicole M, Hafner Marc, Tremblay Julien, Hawley James, Chan Bryan, Verma Vishal A, Beveridge Ramsay E, Hsu Peter L, Ulas Gözde, Wang Lisha, Nonomiya Jim, Chen Shu, Pham Victoria, Webster Joshua, Preston Jessica, Hung Jeff, Eastham Jeff, Dunlap Debra, Lee Wendy, Beroza Paul, Nayyar Naema, Martin Scott, Lin Eva, Weng Julie, Foster Scott A, Shanahan Frances, Fong Rina, Boenig Gladys, Di Lello Paola, Kubala Marta H, Hunsaker Thomas, Ravichandran Mirunalini, Saenz-Lopez Larrocha Pablo, Lau Jeffrey, An Le, Levy Elizabeth, Lorenzo Maria N, Lill Jennie R, Modrusan Zora D, Chen Yi-Chen, Yao Xiaosai, Brastianos Priscilla K, Maddalo Danilo, Dey Anwesha

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Аннотация

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.

Для цитирования: Hagenbeek Thijs J, Zbieg Jason, Smith Russell, Paul Sayantanee, Gerosa Luca, Torrini Consuelo, Guarnaccia Alissa D, Ong Christy, Lacap Jennifer A, Ning Miaoran, Sodir Nicole M, Hafner Marc, Tremblay Julien, Hawley James, Chan Bryan, Verma Vishal A, Beveridge Ramsay E, Hsu Peter L, Ulas Gözde, Wang Lisha, Nonomiya Jim, Chen Shu, Pham Victoria, Webster Joshua, Preston Jessica, Hung Jeff, Eastham Jeff, Dunlap Debra, Lee Wendy, Beroza Paul, Nayyar Naema, Martin Scott, Lin Eva, Weng Julie, Foster Scott A, Shanahan Frances, Fong Rina, Boenig Gladys, Di Lello Paola, Kubala Marta H, Hunsaker Thomas, Ravichandran Mirunalini, Saenz-Lopez Larrocha Pablo, Lau Jeffrey, An Le, Levy Elizabeth, Lorenzo Maria N, Lill Jennie R, Modrusan Zora D, Chen Yi-Chen, Yao Xiaosai, Brastianos Priscilla K, Maddalo Danilo, Dey Anwesha. Covalent pan-TEAD inhibitors block YAP activity and demonstrate brain penetrance in a Hippo-dependent cancer model.. Nature communications. 2026. DOI: 10.1038/s41467-026-74722-5.

Предметные рубрики MeSH

AnimalsHumansTranscription FactorsYAP-Signaling ProteinsCell Line, TumorProtein Serine-Threonine KinasesMiceHippo Signaling PathwayBrainTEA Domain Transcription FactorsAdaptor Proteins, Signal TransducingXenograft Model Antitumor AssaysBrain NeoplasmsSignal TransductionDNA-Binding ProteinsFemaleAntineoplastic AgentsCell Proliferation
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