NIBR-LTSi is a selective LATS kinase inhibitor activating YAP signaling and expanding tissue stem cells in vitro and in vivo

  • Cell Stem Cell. 2024 Apr 4;31(4):554-569.e17. doi: 10.1016/j.stem.2024.03.003.
Kenji Namoto  1 ,  Clara Baader  2 ,  Vanessa Orsini  3 ,  Alexandro Landshammer  3 ,  Eva Breuer  4 ,  Kieu Trinh Dinh  5 ,  Rosemarie Ungricht  3 ,  Monika Pikiolek  3 ,  Stephane Laurent  3 ,  Bo Lu  6 ,  Alexandra Aebi  3 ,  Katharina Schönberger  3 ,  Eric Vangrevelinghe  3 ,  Olivera Evrova  3 ,  Tianliang Sun  7 ,  Stefano Annunziato  3 ,  Julie Lachal  3 ,  Emily Redmond  6 ,  Louis Wang  6 ,  Kristie Wetzel  6 ,  Paola Capodieci  6 ,  Jonathan Turner  3 ,  Gabi Schutzius  3 ,  Vincent Unterreiner  3 ,  Markus Trunzer  3 ,  Nicole Buschmann  3 ,  Dirk Behnke  3 ,  Rainer Machauer  3 ,  Clemens Scheufler  3 ,  Christian N Parker  3 ,  Magali Ferro  3 ,  Armelle Grevot  3 ,  Armin Beyerbach  3 ,  Wei-Yu Lu  8 ,  Stuart J Forbes  9 ,  Jürgen Wagner  3 ,  Tewis Bouwmeester  3 ,  Jun Liu  10 ,  Bindi Sohal  3 ,  Sukhdeep Sahambi  6 ,  Linda E Greenbaum  11 ,  Felix Lohmann  3 ,  Philipp Hoppe  3 ,  Feng Cong  6 ,  Andreas W Sailer  3 ,  Heinz Ruffner  3 ,  Ralf Glatthar  3 ,  Bostjan Humar  4 ,  Pierre-Alain Clavien  4 ,  Michael T Dill  12 ,  Elizabeth George  6 ,  Jürgen Maibaum  3 ,  Prisca Liberali  2 ,  Jan S Tchorz  13
Affiliations
  • 1. Biomedical Research, Novartis Pharma AG, Basel, Switzerland. Electronic address: [email protected].
  • 2. Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland; University of Basel, Basel, Switzerland.
  • 3. Biomedical Research, Novartis Pharma AG, Basel, Switzerland.
  • 4. University Hospital Zurich (USZ), Zurich, Switzerland.
  • 5. German Cancer Research Center (DKFZ) Heidelberg, Research Group Experimental Hepatology, Inflammation and Cancer, Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
  • 6. Biomedical Research, Novartis Pharma AG, Cambridge, MA, USA.
  • 7. Biomedical Research, Novartis Pharma AG, Basel, Switzerland; Division of Liver Diseases, Institute for Regenerative Medicine, Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 8. University of Edinburgh, Center for Inflammation Research, Edinburgh, UK.
  • 9. University of Edinburgh, Center for Regenerative Medicine, Edinburgh, UK.
  • 10. Biomedical Research, Novartis Pharma AG, La Jolla, CA, USA.
  • 11. Biomedical Research, Novartis Pharma AG, East Hanover, NJ, USA.
  • 12. German Cancer Research Center (DKFZ) Heidelberg, Research Group Experimental Hepatology, Inflammation and Cancer, Heidelberg, Germany; Department of Gastroenterology, Infectious Diseases and Intoxication, Heidelberg University Hospital, Heidelberg, Germany.
  • 13. Biomedical Research, Novartis Pharma AG, Basel, Switzerland. Electronic address: [email protected].
PMID: 38579685 DOI: 10.1016/j.stem.2024.03.003
Abstract

The YAP/Hippo pathway is an organ growth and size regulation rheostat safeguarding multiple tissue stem cell compartments. LATS kinases phosphorylate and thereby inactivate YAP, thus representing a potential direct drug target for promoting tissue regeneration. Here, we report the identification and characterization of the selective small-molecule LATS kinase inhibitor NIBR-LTSi. NIBR-LTSi activates YAP signaling, shows good oral bioavailability, and expands organoids derived from several mouse and human tissues. In tissue stem cells, NIBR-LTSi promotes proliferation, maintains stemness, and blocks differentiation in vitro and in vivo. NIBR-LTSi accelerates liver regeneration following extended hepatectomy in mice. However, increased proliferation and cell dedifferentiation in multiple organs prevent prolonged systemic LATS inhibition, thus limiting potential therapeutic benefit. Together, we report a selective LATS kinase inhibitor agonizing YAP signaling and promoting tissue regeneration in vitro and in vivo, enabling future research on the regenerative potential of the YAP/Hippo pathway.

Keywords
LATS kinase inhibitor; YAP agonist; YAP/Hippo pathway; drug development; liver regeneration; organoid expansion; regenerative medicine; tissue regeneration; tissue stem cells; wound healing.
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