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A small molecule inhibitor of Rheb selectively targets mTORC1 signaling

The small G-protein Rheb activates the mechanistic target of rapamycin complex 1 (mTORC1) in response to growth factor signals. mTORC1 is a master regulator of cellular growth and metabolism; aberrant mTORC1 signaling is associated with fibrotic, metabolic, and neurodegenerative diseases, cancers, a...

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Autores principales: Mahoney, Sarah J., Narayan, Sridhar, Molz, Lisa, Berstler, Lauren A., Kang, Seong A., Vlasuk, George P., Saiah, Eddine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803267/
https://www.ncbi.nlm.nih.gov/pubmed/29416044
http://dx.doi.org/10.1038/s41467-018-03035-z
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author Mahoney, Sarah J.
Narayan, Sridhar
Molz, Lisa
Berstler, Lauren A.
Kang, Seong A.
Vlasuk, George P.
Saiah, Eddine
author_facet Mahoney, Sarah J.
Narayan, Sridhar
Molz, Lisa
Berstler, Lauren A.
Kang, Seong A.
Vlasuk, George P.
Saiah, Eddine
author_sort Mahoney, Sarah J.
collection PubMed
description The small G-protein Rheb activates the mechanistic target of rapamycin complex 1 (mTORC1) in response to growth factor signals. mTORC1 is a master regulator of cellular growth and metabolism; aberrant mTORC1 signaling is associated with fibrotic, metabolic, and neurodegenerative diseases, cancers, and rare disorders. Point mutations in the Rheb switch II domain impair its ability to activate mTORC1. Here, we report the discovery of a small molecule (NR1) that binds Rheb in the switch II domain and selectively blocks mTORC1 signaling. NR1 potently inhibits mTORC1 driven phosphorylation of ribosomal protein S6 kinase beta-1 (S6K1) but does not inhibit phosphorylation of AKT or ERK. In contrast to rapamycin, NR1 does not cause inhibition of mTORC2 upon prolonged treatment. Furthermore, NR1 potently and selectively inhibits mTORC1 in mouse kidney and muscle in vivo. The data presented herein suggest that pharmacological inhibition of Rheb is an effective approach for selective inhibition of mTORC1 with therapeutic potential.
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spelling pubmed-58032672018-02-09 A small molecule inhibitor of Rheb selectively targets mTORC1 signaling Mahoney, Sarah J. Narayan, Sridhar Molz, Lisa Berstler, Lauren A. Kang, Seong A. Vlasuk, George P. Saiah, Eddine Nat Commun Article The small G-protein Rheb activates the mechanistic target of rapamycin complex 1 (mTORC1) in response to growth factor signals. mTORC1 is a master regulator of cellular growth and metabolism; aberrant mTORC1 signaling is associated with fibrotic, metabolic, and neurodegenerative diseases, cancers, and rare disorders. Point mutations in the Rheb switch II domain impair its ability to activate mTORC1. Here, we report the discovery of a small molecule (NR1) that binds Rheb in the switch II domain and selectively blocks mTORC1 signaling. NR1 potently inhibits mTORC1 driven phosphorylation of ribosomal protein S6 kinase beta-1 (S6K1) but does not inhibit phosphorylation of AKT or ERK. In contrast to rapamycin, NR1 does not cause inhibition of mTORC2 upon prolonged treatment. Furthermore, NR1 potently and selectively inhibits mTORC1 in mouse kidney and muscle in vivo. The data presented herein suggest that pharmacological inhibition of Rheb is an effective approach for selective inhibition of mTORC1 with therapeutic potential. Nature Publishing Group UK 2018-02-07 /pmc/articles/PMC5803267/ /pubmed/29416044 http://dx.doi.org/10.1038/s41467-018-03035-z Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Mahoney, Sarah J.
Narayan, Sridhar
Molz, Lisa
Berstler, Lauren A.
Kang, Seong A.
Vlasuk, George P.
Saiah, Eddine
A small molecule inhibitor of Rheb selectively targets mTORC1 signaling
title A small molecule inhibitor of Rheb selectively targets mTORC1 signaling
title_full A small molecule inhibitor of Rheb selectively targets mTORC1 signaling
title_fullStr A small molecule inhibitor of Rheb selectively targets mTORC1 signaling
title_full_unstemmed A small molecule inhibitor of Rheb selectively targets mTORC1 signaling
title_short A small molecule inhibitor of Rheb selectively targets mTORC1 signaling
title_sort small molecule inhibitor of rheb selectively targets mtorc1 signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803267/
https://www.ncbi.nlm.nih.gov/pubmed/29416044
http://dx.doi.org/10.1038/s41467-018-03035-z
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