An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance

  • Nat Cancer. 2023 Jun;4(6):812-828. doi: 10.1038/s43018-023-00577-0.
Thijs J Hagenbeek  #  1 ,  Jason R Zbieg  #  2 ,  Marc Hafner  #  3 ,  Rana Mroue  1 ,  Jennifer A Lacap  4 ,  Nicole M Sodir  4 ,  Cameron L Noland  5 ,  Shervin Afghani  1 ,  Ayush Kishore  1 ,  Kamakoti P Bhat  1 ,  Xiaosai Yao  3 ,  Stephen Schmidt  6 ,  Saundra Clausen  6 ,  Micah Steffek  6 ,  Wendy Lee  2 ,  Paul Beroza  2 ,  Scott Martin  1 ,  Eva Lin  1 ,  Rina Fong  5 ,  Paola Di Lello  5 ,  Marta H Kubala  5 ,  Michelle N-Y Yang  4 ,  Jeffrey T Lau  4 ,  Emily Chan  4 ,  Alfonso Arrazate  4 ,  Le An  7 ,  Elizabeth Levy  7 ,  Maria N Lorenzo  8 ,  Ho-June Lee  1 ,  Trang H Pham  1 ,  Zora Modrusan  9 ,  Richard Zang  10 ,  Yi-Chen Chen  10 ,  Michal Kabza  11 ,  Musaddeque Ahmed  12 ,  Jason Li  3 ,  Matthew T Chang  3 ,  Danilo Maddalo  4 ,  Marie Evangelista  13 ,  Xin Ye  14 ,  James J Crawford  15 ,  Anwesha Dey  16
Affiliations
  • 1. Department of Discovery Oncology, Genentech, California, CA, USA.
  • 2. Department of Discovery Chemistry, Genentech, California, CA, USA.
  • 3. Department of Oncology Bioinformatics, Genentech, California, CA, USA.
  • 4. Department of Translational Oncology, Genentech, California, CA, USA.
  • 5. Department of Structural Biology, Genentech, California, CA, USA.
  • 6. Department of Biochemical and Cellular Pharmacology, Genentech, California, CA, USA.
  • 7. Department of Small Molecule Pharmaceutical Sciences, Genentech, California, CA, USA.
  • 8. Department of Protein Chemistry, Genentech, California, CA, USA.
  • 9. Department of Microchemistry, Proteomics and Lipidomics, Genentech, California, CA, USA.
  • 10. Department of Drug Metabolism and Pharmacokinetics, Genentech, California, CA, USA.
  • 11. Roche Polska, Warsaw, Poland.
  • 12. Roche Canada, Mississauga, Ontario, Canada.
  • 13. Department of Discovery Oncology, Genentech, California, CA, USA. [email protected].
  • 14. Department of Discovery Oncology, Genentech, California, CA, USA. [email protected].
  • 15. Department of Discovery Chemistry, Genentech, California, CA, USA. [email protected].
  • 16. Department of Discovery Oncology, Genentech, California, CA, USA. [email protected].
  • # Contributed equally.
PMID: 37277530 DOI: 10.1038/s43018-023-00577-0
Abstract

The Hippo pathway is a key growth control pathway that is conserved across species. The downstream effectors of the Hippo pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), are frequently activated in cancers to drive proliferation and survival. Based on the premise that sustained interactions between YAP/TAZ and TEADs (transcriptional enhanced associate domain) are central to their transcriptional activities, we discovered a potent small-molecule inhibitor (SMI), GNE-7883, that allosterically blocks the interactions between YAP/TAZ and all human TEAD paralogs through binding to the TEAD lipid pocket. GNE-7883 effectively reduces chromatin accessibility specifically at TEAD motifs, suppresses cell proliferation in a variety of cell line models and achieves strong antitumor efficacy in vivo. Furthermore, we uncovered that GNE-7883 effectively overcomes both intrinsic and acquired resistance to KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C inhibitors in diverse preclinical models through the inhibition of YAP/TAZ activation. Taken together, this work demonstrates the activities of TEAD SMIs in YAP/TAZ-dependent cancers and highlights their potential broad applications in precision oncology and therapy resistance.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-147214
    GNE-7883
    99.54%, pan-TEAD Inhibitor
    target: YAP
    Research Areas: Cancer