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<p>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<sup>G12C</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月27日

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  • 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

摘要

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.