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

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; Jan S. Tchorz

doi:10.1016/j.stem.2024.03.003

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

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 WetzelPaola 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, Jan S. Tchorz

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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.

Original language	English
Pages (from-to)	554-569.e17
Journal	Cell Stem Cell
Volume	31
Issue number	4
DOIs	https://doi.org/10.1016/j.stem.2024.03.003
State	Published - 4 Apr 2024

Keywords

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

Access to Document

10.1016/j.stem.2024.03.003

Cite this

Namoto, K., Baader, C., Orsini, V., Landshammer, A., Breuer, E., Dinh, K. T., Ungricht, R., Pikiolek, M., Laurent, S., Lu, B., Aebi, A., Schönberger, K., Vangrevelinghe, E., Evrova, O., Sun, T., Annunziato, S., Lachal, J., Redmond, E., Wang, L., ... Tchorz, J. S. (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, 31(4), 554-569.e17. https://doi.org/10.1016/j.stem.2024.03.003

@article{d57012f896784eedb51998b772e50c08,

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

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",

author = "Kenji Namoto and Clara Baader and Vanessa Orsini and Alexandro Landshammer and Eva Breuer and Dinh, {Kieu Trinh} and Rosemarie Ungricht and Monika Pikiolek and Stephane Laurent and Bo Lu and Alexandra Aebi and Katharina Sch{\"o}nberger and Eric Vangrevelinghe and Olivera Evrova and Tianliang Sun and Stefano Annunziato and Julie Lachal and Emily Redmond and Louis Wang and Kristie Wetzel and Paola Capodieci and Jonathan Turner and Gabi Schutzius and Vincent Unterreiner and Markus Trunzer and Nicole Buschmann and Dirk Behnke and Rainer Machauer and Clemens Scheufler and Parker, {Christian N.} and Magali Ferro and Armelle Grevot and Armin Beyerbach and Lu, {Wei Yu} and Forbes, {Stuart J.} and J{\"u}rgen Wagner and Tewis Bouwmeester and Jun Liu and Bindi Sohal and Sukhdeep Sahambi and Greenbaum, {Linda E.} and Felix Lohmann and Philipp Hoppe and Feng Cong and Sailer, {Andreas W.} and Heinz Ruffner and Ralf Glatthar and Bostjan Humar and Clavien, {Pierre Alain} and Dill, {Michael T.} and Elizabeth George and J{\"u}rgen Maibaum and Prisca Liberali and Tchorz, {Jan S.}",

note = "Publisher Copyright: {\textcopyright} 2024 Elsevier Inc.",

year = "2024",

month = apr,

day = "4",

doi = "10.1016/j.stem.2024.03.003",

language = "English",

volume = "31",

pages = "554--569.e17",

journal = "Cell Stem Cell",

issn = "1934-5909",

publisher = "Cell Press",

number = "4",

}

Namoto, K, Baader, C, Orsini, V, Landshammer, A, Breuer, E, Dinh, KT, Ungricht, R, Pikiolek, M, Laurent, S, Lu, B, Aebi, A, Schönberger, K, Vangrevelinghe, E, Evrova, O, Sun, T, Annunziato, S, Lachal, J, Redmond, E, Wang, L, Wetzel, K, Capodieci, P, Turner, J, Schutzius, G, Unterreiner, V, Trunzer, M, Buschmann, N, Behnke, D, Machauer, R, Scheufler, C, Parker, CN, Ferro, M, Grevot, A, Beyerbach, A, Lu, WY, Forbes, SJ, Wagner, J, Bouwmeester, T, Liu, J, Sohal, B, Sahambi, S, Greenbaum, LE, Lohmann, F, Hoppe, P, Cong, F, Sailer, AW, Ruffner, H, Glatthar, R, Humar, B, Clavien, PA, Dill, MT, George, E, Maibaum, J, Liberali, P & Tchorz, JS 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, vol. 31, no. 4, pp. 554-569.e17. https://doi.org/10.1016/j.stem.2024.03.003

TY - JOUR

T1 - NIBR-LTSi is a selective LATS kinase inhibitor activating YAP signaling and expanding tissue stem cells in vitro and in vivo

AU - Namoto, Kenji

AU - Baader, Clara

AU - Orsini, Vanessa

AU - Landshammer, Alexandro

AU - Breuer, Eva

AU - Dinh, Kieu Trinh

AU - Ungricht, Rosemarie

AU - Pikiolek, Monika

AU - Laurent, Stephane

AU - Lu, Bo

AU - Aebi, Alexandra

AU - Schönberger, Katharina

AU - Vangrevelinghe, Eric

AU - Evrova, Olivera

AU - Sun, Tianliang

AU - Annunziato, Stefano

AU - Lachal, Julie

AU - Redmond, Emily

AU - Wang, Louis

AU - Wetzel, Kristie

AU - Capodieci, Paola

AU - Turner, Jonathan

AU - Schutzius, Gabi

AU - Unterreiner, Vincent

AU - Trunzer, Markus

AU - Buschmann, Nicole

AU - Behnke, Dirk

AU - Machauer, Rainer

AU - Scheufler, Clemens

AU - Parker, Christian N.

AU - Ferro, Magali

AU - Grevot, Armelle

AU - Beyerbach, Armin

AU - Lu, Wei Yu

AU - Forbes, Stuart J.

AU - Wagner, Jürgen

AU - Bouwmeester, Tewis

AU - Liu, Jun

AU - Sohal, Bindi

AU - Sahambi, Sukhdeep

AU - Greenbaum, Linda E.

AU - Lohmann, Felix

AU - Hoppe, Philipp

AU - Cong, Feng

AU - Sailer, Andreas W.

AU - Ruffner, Heinz

AU - Glatthar, Ralf

AU - Humar, Bostjan

AU - Clavien, Pierre Alain

AU - Dill, Michael T.

AU - George, Elizabeth

AU - Maibaum, Jürgen

AU - Liberali, Prisca

AU - Tchorz, Jan S.

PY - 2024/4/4

Y1 - 2024/4/4

N2 - 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.

AB - 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.

KW - LATS kinase inhibitor

KW - YAP agonist

KW - YAP/Hippo pathway

KW - drug development

KW - liver regeneration

KW - organoid expansion

KW - regenerative medicine

KW - tissue regeneration

KW - tissue stem cells

KW - wound healing

UR - http://www.scopus.com/inward/record.url?scp=85189518416&partnerID=8YFLogxK

U2 - 10.1016/j.stem.2024.03.003

DO - 10.1016/j.stem.2024.03.003

M3 - Article

AN - SCOPUS:85189518416

SN - 1934-5909

VL - 31

SP - 554-569.e17

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 4

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this