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

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...

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Main Authors: Namoto, Kenji (Author) , Baader, Clara (Author) , Orsini, Vanessa (Author) , Landshammer, Alexandro (Author) , Breuer, Eva (Author) , Dinh, Kieu Trinh (Author) , Ungricht, Rosemarie (Author) , Pikiolek, Monika (Author) , Laurent, Stephane (Author) , Lu, Bo (Author) , Aebi, Alexandra (Author) , Schönberger, Katharina (Author) , Vangrevelinghe, Eric (Author) , Evrova, Olivera (Author) , Sun, Tianliang (Author) , Annunziato, Stefano (Author) , Lachal, Julie (Author) , Redmond, Emily (Author) , Wang, Louis (Author) , Wetzel, Kristie (Author) , Capodieci, Paola (Author) , Turner, Jonathan (Author) , Schutzius, Gabi (Author) , Unterreiner, Vincent (Author) , Trunzer, Markus (Author) , Buschmann, Nicole (Author) , Behnke, Dirk (Author) , Machauer, Rainer (Author) , Scheufler, Clemens (Author) , Parker, Christian N. (Author) , Ferro, Magali (Author) , Grevot, Armelle (Author) , Beyerbach, Armin (Author) , Lu, Wei-Yu (Author) , Forbes, Stuart J. (Author) , Wagner, Jürgen (Author) , Bouwmeester, Tewis (Author) , Liu, Jun (Author) , Sohal, Bindi (Author) , Sahambi, Sukhdeep (Author) , Greenbaum, Linda E. (Author) , Lohmann, Felix (Author) , Hoppe, Philipp (Author) , Cong, Feng (Author) , Sailer, Andreas W. (Author) , Ruffner, Heinz (Author) , Glatthar, Ralf (Author) , Humar, Bostjan (Author) , Clavien, Pierre-Alain (Author) , Dill, Michael T. (Author) , George, Elizabeth (Author) , Maibaum, Jürgen (Author) , Liberali, Prisca (Author) , Tchorz, Jan S. (Author)
Format: Article (Journal)
Language:English
Published: 4 April 2024
In: Cell stem cell
Year: 2024, Volume: 31, Issue: 4, Pages: 554–569.e1-e17
ISSN:1875-9777
DOI:10.1016/j.stem.2024.03.003
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.stem.2024.03.003
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S1934590924000845
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Author Notes:Kenji Namoto, Clara Baader, Vanessa Orsini, Alexandro Landshammer, Eva Breuer, Kieu Trinh Dinh, Rosemarie Ungricht, Monika Pikiolek, Stephane Laurent, Bo Lu, Alexandra Aebi, Katharina Schönberger, Eric Vangrevelinghe, Olivera Evrova, Tianliang Sun, Stefano Annunziato, Julie Lachal, Emily Redmond, Louis Wang, Kristie Wetzel, Paola Capodieci, Jonathan Turner, Gabi Schutzius, Vincent Unterreiner, Markus Trunzer, Nicole Buschmann, Dirk Behnke, Rainer Machauer, Clemens Scheufler, Christian N. Parker, Magali Ferro, Armelle Grevot, Armin Beyerbach, Wei-Yu Lu, Stuart J. Forbes, Jürgen Wagner, Tewis Bouwmeester, Jun Liu, Bindi Sohal, Sukhdeep Sahambi, Linda E. Greenbaum, Felix Lohmann, Philipp Hoppe, Feng Cong, Andreas W. Sailer, Heinz Ruffner, Ralf Glatthar, Bostjan Humar, Pierre-Alain Clavien, Michael T. Dill, Elizabeth George, Jürgen Maibaum, Prisca Liberali, and Jan S. Tchorz
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Summary: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.
Item Description:Online verfügbar 4 April 2024, Version des Artikels 4 April 2024
Gesehen am 10.03.2025
Physical Description:Online Resource
ISSN:1875-9777
DOI:10.1016/j.stem.2024.03.003

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