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Structure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in mice
Osteoporosis is a major public health problem. Currently, there are no orally available therapies that increase bone formation. Intermittent parathyroid hormone (PTH) stimulates bone formation through a signal transduction pathway that involves inhibition of salt-inducible kinase isoforms 2 and 3 (S...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9897432/ https://www.ncbi.nlm.nih.gov/pubmed/36472957 http://dx.doi.org/10.1073/pnas.2214396119 |
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author | Sato, Tadatoshi Andrade, Christian D. Castro Yoon, Sung-Hee Zhao, Yingshe Greenlee, William J. Weber, Patricia C. Viswanathan, Usha Kulp, John Brooks, Daniel J. Demay, Marie B. Bouxsein, Mary L. Mitlak, Bruce Lanske, Beate Wein, Marc N. |
author_facet | Sato, Tadatoshi Andrade, Christian D. Castro Yoon, Sung-Hee Zhao, Yingshe Greenlee, William J. Weber, Patricia C. Viswanathan, Usha Kulp, John Brooks, Daniel J. Demay, Marie B. Bouxsein, Mary L. Mitlak, Bruce Lanske, Beate Wein, Marc N. |
author_sort | Sato, Tadatoshi |
collection | PubMed |
description | Osteoporosis is a major public health problem. Currently, there are no orally available therapies that increase bone formation. Intermittent parathyroid hormone (PTH) stimulates bone formation through a signal transduction pathway that involves inhibition of salt-inducible kinase isoforms 2 and 3 (SIK2 and SIK3). Here, we further validate SIK2/SIK3 as osteoporosis drug targets by demonstrating that ubiquitous deletion of these genes in adult mice increases bone formation without extraskeletal toxicities. Previous efforts to target these kinases to stimulate bone formation have been limited by lack of pharmacologically acceptable, specific, orally available SIK2/SIK3 inhibitors. Here, we used structure-based drug design followed by iterative medicinal chemistry to identify SK-124 as a lead compound that potently inhibits SIK2 and SIK3. SK-124 inhibits SIK2 and SIK3 with single-digit nanomolar potency in vitro and in cell-based target engagement assays and shows acceptable kinome selectivity and oral bioavailability. SK-124 reduces SIK2/SIK3 substrate phosphorylation levels in human and mouse cultured bone cells and regulates gene expression patterns in a PTH-like manner. Once-daily oral SK-124 treatment for 3 wk in mice led to PTH-like effects on mineral metabolism including increased blood levels of calcium and 1,25-vitamin D and suppressed endogenous PTH levels. Furthermore, SK-124 treatment increased bone formation by osteoblasts and boosted trabecular bone mass without evidence of short-term toxicity. Taken together, these findings demonstrate PTH-like effects in bone and mineral metabolism upon in vivo treatment with orally available SIK2/SIK3 inhibitor SK-124. |
format | Online Article Text |
id | pubmed-9897432 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-98974322023-02-04 Structure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in mice Sato, Tadatoshi Andrade, Christian D. Castro Yoon, Sung-Hee Zhao, Yingshe Greenlee, William J. Weber, Patricia C. Viswanathan, Usha Kulp, John Brooks, Daniel J. Demay, Marie B. Bouxsein, Mary L. Mitlak, Bruce Lanske, Beate Wein, Marc N. Proc Natl Acad Sci U S A Biological Sciences Osteoporosis is a major public health problem. Currently, there are no orally available therapies that increase bone formation. Intermittent parathyroid hormone (PTH) stimulates bone formation through a signal transduction pathway that involves inhibition of salt-inducible kinase isoforms 2 and 3 (SIK2 and SIK3). Here, we further validate SIK2/SIK3 as osteoporosis drug targets by demonstrating that ubiquitous deletion of these genes in adult mice increases bone formation without extraskeletal toxicities. Previous efforts to target these kinases to stimulate bone formation have been limited by lack of pharmacologically acceptable, specific, orally available SIK2/SIK3 inhibitors. Here, we used structure-based drug design followed by iterative medicinal chemistry to identify SK-124 as a lead compound that potently inhibits SIK2 and SIK3. SK-124 inhibits SIK2 and SIK3 with single-digit nanomolar potency in vitro and in cell-based target engagement assays and shows acceptable kinome selectivity and oral bioavailability. SK-124 reduces SIK2/SIK3 substrate phosphorylation levels in human and mouse cultured bone cells and regulates gene expression patterns in a PTH-like manner. Once-daily oral SK-124 treatment for 3 wk in mice led to PTH-like effects on mineral metabolism including increased blood levels of calcium and 1,25-vitamin D and suppressed endogenous PTH levels. Furthermore, SK-124 treatment increased bone formation by osteoblasts and boosted trabecular bone mass without evidence of short-term toxicity. Taken together, these findings demonstrate PTH-like effects in bone and mineral metabolism upon in vivo treatment with orally available SIK2/SIK3 inhibitor SK-124. National Academy of Sciences 2022-12-06 2022-12-13 /pmc/articles/PMC9897432/ /pubmed/36472957 http://dx.doi.org/10.1073/pnas.2214396119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Sato, Tadatoshi Andrade, Christian D. Castro Yoon, Sung-Hee Zhao, Yingshe Greenlee, William J. Weber, Patricia C. Viswanathan, Usha Kulp, John Brooks, Daniel J. Demay, Marie B. Bouxsein, Mary L. Mitlak, Bruce Lanske, Beate Wein, Marc N. Structure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in mice |
title | Structure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in mice |
title_full | Structure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in mice |
title_fullStr | Structure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in mice |
title_full_unstemmed | Structure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in mice |
title_short | Structure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in mice |
title_sort | structure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in mice |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9897432/ https://www.ncbi.nlm.nih.gov/pubmed/36472957 http://dx.doi.org/10.1073/pnas.2214396119 |
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