ArticleProceedings of the National Academy of Sciences of the United States of America2024
Identification of highly selective SIK1/2 inhibitors that modulate innate immune activation and suppress intestinal inflammation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers, 1 of them a synthesis that pooled it.
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The trial behind it
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Who cites it
11 citing papers in PubMed, 1 synthesis or guideline pooled it, 21 citations in OpenAlex.
- Brain connectivity changes associated with acute sleep deprivation: a systematic review.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Pooled it
- Structure-Activity Relationship Studies Resulting in the Identification of Potent and Selective Salt-Inducible Kinase Inhibitors.ACS medicinal chemistry letters · 2026Article
- Selective SIK2/SIK3 inhibition reprograms pro- and antiinflammatory pathways in myeloid cells, improving autoimmune disease outcomes.JCI insight · 2026Article
- High-Quality In Vivo Chemical Probes for Protein Kinases Disclosed in 2024.ACS pharmacology & translational science · 2025Review
- The Role of the Salt-inducible Kinases in the Endocrine Glands.Endocrinology · 2025Review
- Salt-inducible Kinase Regulation of Adipose Tissue Metabolism.Endocrinology · 2025Review
- Inhibition of SIK1 Alleviates the Pathologies of Psoriasis by Disrupting IL-17 Signaling.Mediators of inflammation · 2025Article
- Role of SIK1 in tumors: Emerging players and therapeutic potentials (Review).Oncology reports · 2024Review
- 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
- Stimulation of fracture mineralization by salt-inducible kinase inhibitors.Frontiers in bioengineering and biotechnology · 2024Article
- Understanding the roles of salt-inducible kinases in cardiometabolic disease.Frontiers in physiology · 2024Review
Corrections and comments
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Authors and funding
44 authors at 2 institutions in 1 country.
Funding
Abstract
The salt-inducible kinases (SIK) 1-3 are key regulators of pro- versus anti-inflammatory cytokine responses during innate immune activation. The lack of highly SIK-family or SIK isoform-selective inhibitors suitable for repeat, oral dosing has limited the study of the optimal SIK isoform selectivity profile for suppressing inflammation in vivo. To overcome this challenge, we devised a structure-based design strategy for developing potent SIK inhibitors that are highly selective against other kinases by engaging two differentiating features of the SIK catalytic site. This effort resulted in SIK1/2-selective probes that inhibit key intracellular proximal signaling events including reducing phosphorylation of the SIK substrate cAMP response element binding protein (CREB) regulated transcription coactivator 3 (CRTC3) as detected with an internally generated phospho-Ser329-CRTC3-specific antibody. These inhibitors also suppress production of pro-inflammatory cytokines while inducing anti-inflammatory interleukin-10 in activated human and murine myeloid cells and in mice following a lipopolysaccharide challenge. Oral dosing of these compounds ameliorates disease in a murine colitis model. These findings define an approach to generate highly selective SIK1/2 inhibitors and establish that targeting these isoforms may be a useful strategy to suppress pathological inflammation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.