bims-sikglu Biomed News
on Salt inducible kinases in glucose metabolism
Issue of 2026–08–23
two papers selected by
Dipsikha Biswas, Københavns Universitet and Maria Madrazo i Montoya, Københavns Universitet
  1. Inhibition of Salt-Inducible Kinases 2 and 3 reduces inflammatory signature in Psoriasis.
  2. Structure-Activity Relationship Studies Resulting in the Identification of Potent and Selective Salt-Inducible Kinase Inhibitors.
  1. J Invest Dermatol. 2026 Aug 18. pii: S0022-202X(26)02740-5. [Epub ahead of print]
    Inhibition of Salt-Inducible Kinases 2 and 3 reduces inflammatory signature in Psoriasis.
    Anna Caroline Pilz, Eva Briem, Maikel Colli, Christina Hillig, Stephanie Lavazais, Michael P Menden, Tilo Biedermann, Felix Lauffer, Kilian Eyerich, Steve De Vos, Manja Jargosch.
      Psoriasis is a highly prevalent inflammatory skin disease for which good systemic therapeutic agents are available. However, there still is a great need for new treatment options, especially oral ones. Salt-inducible kinases (SIKs) are emerging as new druggable targets in immune diseases and the SIK2/SIK3 inhibitor GLPG3970 recently proved to efficiently reduce psoriasis lesions in a phase Ib trial. This study assesses molecular events underlying beneficial effects of SIK2/SIK3 inhibition via GLPG3970 in psoriasis. Using spatial transcriptomics and single cell sequencing, abundant expression of SIK2 and SIK3, but not of SIK1, was observed in psoriatic skin. In vitro, GLPG3970 reduced psoriasis marker cytokines and chemokines (TNF, IFN-γ, IL-1β, IL-6, CXCL8, CXCL10) in peripheral mononuclear cells, T cells and fibroblasts, but not in keratinocytes. Bulk RNA sequencing of lesional psoriasis biopsies treated ex vivo with GLPG3970 and of biopsies received from responders vs. placebo-treated patients of the clinical trial showed downregulation of inflammatory pathways with suppression of IL1B, CXCL1, CXCL8, CEBPB, CD177, and CLEC5A in both settings. In summary, this study suggests that specific inhibition of SIK2/SIK3 reduces acute phase immunity and neutrophil recruitment in psoriasis.
    Keywords:  Acute inflammation; Dendritic cells; Macrophages; Monocytes; Neutrophils
    DOI:  https://doi.org/10.1016/j.jid.2026.07.033
  2. ACS Med Chem Lett. 2026 Aug 13. 17(8): 1795-1805
    Structure-Activity Relationship Studies Resulting in the Identification of Potent and Selective Salt-Inducible Kinase Inhibitors.
    Daniel T Webb, Katherine L Jones, Gerald Keil, Matthew Holt, Nicholas Richards, Yvonne Walker, Andrea Taylor, Maryam Ahmadi, Lampros Milanos, Natsuko Macabuag, Eilidh Bush, Matthew Gill, Rebecca Penrose, David M Lindsay, William J Kerr, William Esmieu.
      Salt-inducible kinases (SIK1/2/3) belong to the AMPK family of serine/threonine kinases, and SIK inhibition has been identified as a promising strategy for therapeutic intervention in oncology and immunology. Herein, we describe the use of parallel chemistry approaches to facilitate the development of novel SIK inhibitors. From these efforts, potent pan-SIK inhibitors were identified, as well as compounds which demonstrated biased isoform selectivity toward SIK3, and possessed attractive in vitro ADME properties. To validate the most promising compounds as high-quality chemical tools, cellular target engagement was assessed using NanoBRET assays, and selectivity was investigated across the wider kinome. Finally, the pharmacological effects of several compounds were studied using cellular models of acute myeloid leukemia, resulting in the identification of potent antiproliferative agents. The compounds reported represent high-quality chemical tools of potential value for target validation studies and could serve as effective starting points for a lead optimization campaign.
    DOI:  https://doi.org/10.1021/acsmedchemlett.6c00199
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