ArticleProceedings of the National Academy of Sciences of the United States of America2022
Structure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in mice.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 33 citations in OpenAlex.
- Structure-Activity Relationship Studies Resulting in the Identification of Potent and Selective Salt-Inducible Kinase Inhibitors.ACS medicinal chemistry letters · 2026Article
- The orally available SIK2/SIK3 inhibitor SK-124 increases bone mass in hypogonadal male mice.JBMR plus · 2026Article
- G protein-coupled receptor signaling in osteogenic bone mesenchymal stem/stromal cells.Frontiers in cell and developmental biology · 2026Review
- High-Quality In Vivo Chemical Probes for Protein Kinases Disclosed in 2024.ACS pharmacology & translational science · 2025Review
- Salt-inducible Kinase Regulation of Adipose Tissue Metabolism.Endocrinology · 2025Review
- DNAJB1-PRKACA Fusion Drives Fibrolamellar Liver Cancer through Impaired SIK Signaling and CRTC2/p300-Mediated Transcriptional Reprogramming.Cancer discovery · 2025Article
- Discovery of Clinical Candidate GLPG3970: A Potent and Selective Dual SIK2/SIK3 Inhibitor for the Treatment of Autoimmune and Inflammatory Diseases.Journal of medicinal chemistry · 2024Article
- Potential therapeutic role of spermine via Rac1 in osteoporosis: Insights from zebrafish and mice.Zoological research · 2024Article
- Optimization of Selectivity and Pharmacokinetic Properties of Salt-Inducible Kinase Inhibitors that Led to the Discovery of Pan-SIK Inhibitor GLPG3312.Journal of medicinal chemistry · 2024Article
- Synthesis and cytotoxic activity evaluation of novel imidazopyridine carbohydrazide derivatives.BMC chemistry · 2024Article
- Identification of highly selective SIK1/2 inhibitors that modulate innate immune activation and suppress intestinal inflammation.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Bone and bone derived factors in kidney disease.Frontiers in physiology · 2024Review
- Understanding the roles of salt-inducible kinases in cardiometabolic disease.Frontiers in physiology · 2024Review
- Stimulation of fracture mineralization by salt-inducible kinase inhibitors.Frontiers in bioengineering and biotechnology · 2024Article
- The multiple roles of salt-inducible kinases in regulating physiology.Physiological reviews · 2023Review
- A parathyroid hormone/salt-inducible kinase signaling axis controls renal vitamin D activation and organismal calcium homeostasis.The Journal of clinical investigation · 2023Article
- Renal proximal tubule cells: power and finesse.The Journal of clinical investigation · 2023Article
- Parathyroid Hormone-Related Protein/Parathyroid Hormone Receptor 1 Signaling in Cancer and Metastasis.Cancers · 2023Review
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Authors and funding
14 authors at 5 institutions in 1 country.
Funding
Abstract
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.
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