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

  • Nat Commun. 2026 Jun 27. doi: 10.1038/s41467-026-74722-5.
Thijs J Hagenbeek  #  1 ,  Jason Zbieg  #  2 ,  Russell Smith  #  2 ,  Sayantanee Paul  #  1 ,  Luca Gerosa  #  3 ,  Consuelo Torrini  4 ,  Alissa D Guarnaccia  1  5 ,  Christy Ong  1 ,  Jennifer A Lacap  6 ,  Miaoran Ning  7 ,  Nicole M Sodir  6 ,  Marc Hafner  3 ,  Julien Tremblay  3 ,  James Hawley  3 ,  Bryan Chan  2 ,  Vishal A Verma  2 ,  Ramsay E Beveridge  8 ,  Peter L Hsu  9 ,  Gözde Ulas  10 ,  Lisha Wang  10 ,  Jim Nonomiya  10 ,  Shu Chen  7 ,  Victoria Pham  5 ,  Joshua Webster  11 ,  Jessica Preston  11 ,  Jeff Hung  11 ,  Jeff Eastham  11 ,  Debra Dunlap  11 ,  Wendy Lee  2 ,  Paul Beroza  2 ,  Naema Nayyar  4 ,  Scott Martin  1 ,  Eva Lin  1 ,  Julie Weng  1 ,  Scott A Foster  1 ,  Frances Shanahan  1 ,  Rina Fong  9 ,  Gladys Boenig  9 ,  Paola Di Lello  9 ,  Marta H Kubala  9 ,  Thomas Hunsaker  6 ,  Mirunalini Ravichandran  6 ,  Pablo Saenz-Lopez Larrocha  6 ,  Jeffrey Lau  6 ,  Le An  12 ,  Elizabeth Levy  12 ,  Maria N Lorenzo  13 ,  Jennie R Lill  5 ,  Zora D Modrusan  5 ,  Yi-Chen Chen  7 ,  Xiaosai Yao  3 ,  Priscilla K Brastianos  4 ,  Danilo Maddalo  #  14 ,  Anwesha Dey  #  15
Affiliations
  • 1. Department of Discovery Oncology, Genentech, South San Francisco, CA, USA.
  • 2. Department of Discovery Chemistry, Genentech, South San Francisco, CA, USA.
  • 3. Department of gRED Computational Sciences, Genentech, South San Francisco, CA, USA.
  • 4. Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • 5. Department of Proteomic and Genomic Technologies, Genentech, South San Francisco, CA, USA.
  • 6. Department of Translational Oncology, Genentech, South San Francisco, CA, USA.
  • 7. Department of Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, CA, USA.
  • 8. Paraza Pharma Inc, Montreal, QC, Canada.
  • 9. Department of Structural Biology, Genentech, South San Francisco, CA, USA.
  • 10. Department of Biochemical and Cellular Pharmacology, Genentech, South San Francisco, CA, USA.
  • 11. Department of Research Pathology, Genentech, South San Francisco, CA, USA.
  • 12. Department of Small Molecule Pharmaceutical Sciences, Genentech, South San Francisco, CA, USA.
  • 13. Department of Protein Chemistry, Genentech, South San Francisco, CA, USA.
  • 14. Department of Translational Oncology, Genentech, South San Francisco, CA, USA. [email protected].
  • 15. Department of Discovery Oncology, Genentech, South San Francisco, CA, USA. [email protected].
  • # Contributed equally.
PMID: 42365001 DOI: 10.1038/s41467-026-74722-5
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 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.

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