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dc.contributor.authorSato, Tadatoshi
dc.contributor.authorAndrade, Christian D Castro
dc.contributor.authorYoon, Sung-Hee
dc.contributor.authorZhao, Yingshe
dc.contributor.authorGreenlee, William J
dc.contributor.authorWeber, Patricia C
dc.contributor.authorViswanathan, Usha
dc.contributor.authorKulp, John
dc.contributor.authorBrooks, Daniel J
dc.contributor.authorDemay, Marie B
dc.contributor.authorBouxsein, Mary L
dc.contributor.authorMitlak, Bruce
dc.contributor.authorLanske, Beate
dc.contributor.authorWein, Marc N
dc.date.accessioned2024-04-26T20:16:18Z
dc.date.available2024-04-26T20:16:18Z
dc.date.issued2022-12-06
dc.identifier.citationSato T, Andrade CDC, Yoon SH, Zhao Y, Greenlee WJ, Weber PC, Viswanathan U, Kulp J, Brooks DJ, Demay MB, Bouxsein ML, Mitlak B, Lanske B, Wein MN. Structure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in mice. Proc Natl Acad Sci U S A. 2022 Dec 13;119(50):e2214396119. doi: 10.1073/pnas.2214396119. Epub 2022 Dec 6. PMID: 36472957; PMCID: PMC9897432.en_US
dc.identifier.eissn1091-6490
dc.identifier.doi10.1073/pnas.2214396119en_US
dc.identifier.pmid36472957
dc.identifier.urihttp://hdl.handle.net/20.500.14038/53320
dc.description.abstractOsteoporosis 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.en_US
dc.language.isoenen_US
dc.relation.ispartofProceedings of the National Academy of Sciencesen_US
dc.relation.urlhttps://doi.org/10.1073/pnas.2214396119en_US
dc.rightsCopyright © 2022 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).en_US
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectkinase inhibitoren_US
dc.subjectosteoporosisen_US
dc.subjectparathyroid hormoneen_US
dc.titleStructure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in miceen_US
dc.typeJournal Articleen_US
dc.source.journaltitleProceedings of the National Academy of Sciences of the United States of America
dc.source.volume119
dc.source.issue50
dc.source.beginpagee2214396119
dc.source.endpage
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.identifier.journalProceedings of the National Academy of Sciences of the United States of America
refterms.dateFOA2024-04-26T20:16:19Z
dc.contributor.departmentHorae Gene Therapy Centeren_US
dc.contributor.departmentMedicineen_US


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Copyright © 2022 the Author(s). Published by PNAS.
This open access article is distributed under Creative
Commons Attribution-NonCommercial-NoDerivatives
License 4.0 (CC BY-NC-ND).
Except where otherwise noted, this item's license is described as Copyright © 2022 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).