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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,12,13]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1073\/pnas.2214396119","type":"journal-article","created":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T13:08:19Z","timestamp":1670332099000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":36,"title":["Structure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in mice"],"prefix":"10.1073","volume":"119","author":[{"given":"Tadatoshi","family":"Sato","sequence":"first","affiliation":[{"name":"Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114"},{"name":"Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655"},{"name":"Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian D. Castro","family":"Andrade","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung-Hee","family":"Yoon","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingshe","family":"Zhao","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"Greenlee","sequence":"additional","affiliation":[{"name":"Harrington Discovery Institute, University Hospitals, Cleveland, OH 44106"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia C.","family":"Weber","sequence":"additional","affiliation":[{"name":"Harrington Discovery Institute, University Hospitals, Cleveland, OH 44106"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Usha","family":"Viswanathan","sequence":"additional","affiliation":[{"name":"Conifer Point, Doylestown, PA 18902"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2586-9207","authenticated-orcid":false,"given":"John","family":"Kulp","sequence":"additional","affiliation":[{"name":"Conifer Point, Doylestown, PA 18902"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Brooks","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie B.","family":"Demay","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary L.","family":"Bouxsein","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7050-0703","authenticated-orcid":false,"given":"Bruce","family":"Mitlak","sequence":"additional","affiliation":[{"name":"Radius Health Inc., Boston, MA 02210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beate","family":"Lanske","sequence":"additional","affiliation":[{"name":"Radius Health Inc., Boston, MA 02210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6015-8147","authenticated-orcid":false,"given":"Marc N.","family":"Wein","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114"},{"name":"Broad Institute of MIT and Harvard, Cambridge, MA 02142"},{"name":"Harvard Stem Cell Institute, Cambridge, MA 02138"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,12,6]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(02)08657-9"},{"key":"e_1_3_4_2_2","first-page":"2005","article-title":"NCHS Data Brief: Osteoporosis or Low Bone Mass at the Femur Neck or Lumbar Spine in Older Adults: United States","volume":"93","author":"Looker A.","year":"2012","unstructured":"A. Looker , NCHS Data Brief: Osteoporosis or Low Bone Mass at the Femur Neck or Lumbar Spine in Older Adults: United States. NCHS Centers Dis. Control Prev. 93, 2005\u20132008 (2012).","journal-title":"NCHS Centers Dis. Control Prev."},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2019.15781"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.4158\/EP161435.GL"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.7326\/M15-1361"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11914-017-0353-4"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)02646-5"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aay6570"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2019.07.011"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/jbm4.10367"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.abc5944"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-021-00929-w"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13384"},{"key":"e_1_3_4_14_2","first-page":"100097","article-title":"The combined effect of permeation enhancement and proteolysis inhibition on the systemic exposure of orally administrated peptides: Salcaprozate sodium, soybean trypsin inhibitor, and teriparatide study in pigs","volume":"3","author":"Burshtein G.","year":"2021","unstructured":"G. Burshtein , The combined effect of permeation enhancement and proteolysis inhibition on the systemic exposure of orally administrated peptides: Salcaprozate sodium, soybean trypsin inhibitor, and teriparatide study in pigs. X 3, 100097 (2021).","journal-title":"X"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.4274"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-0760(03)00199-7"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20200502"},{"key":"e_1_3_4_18_2","first-page":"827","article-title":"The salt-inducible kinases: Emerging metabolic regulators","volume":"29","author":"Sakamoto K.","year":"2018","unstructured":"K. Sakamoto, L. Bultot, O. Goransson, The salt-inducible kinases: Emerging metabolic regulators. 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