Namoto, Kenji, Ungricht, Rosemarie, Pikiolek, Monika, Orsini, Vanessa, Laurent, Stephane, Vangrevelinghe, Eric, Sun, Tianliang, Lachal, Julie, Redmond, Emily, Wang, Louis, Wetzel, Kristie, Capodieci, Paola, Turner, Jonathan, Aebi, Alexandra, Schutzius, Gabi, Unterreiner, Vincent, Trunzer, Markus, Buschmann, Nicole, Behnke, Dirk, Machauer, Rainer, Scheufler, Clemens, Wagner, Juergen, Bouwmeester, Antonius, Liu, Jun, Sahambi, Sukhdeep, Greenbaum, Linda, Lohmann, Felix, Hoppe, Philipp, Ruffner, Heinz, Sailer, Andreas, George, Elizabeth, Glatthar, Ralf and Liberali, Prisca (2024) NIBR-LTSi is a selective LATS kinase inhibitor activating YAP signaling and expanding tissue stem cells in vitro and in vivo. Cell Stem Cell.

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 the initiation of liver regeneration following partial hepatectomy in mice. However, adverse effects in gut and kidney 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 Type:	Article
Date Deposited:	01 Oct 2024 00:45
Last Modified:	01 Oct 2024 00:45
URI:	https://oak.novartis.com/id/eprint/52688