Inhibition of Salt-Inducible Kinases 2 and 3 reduces inflammatory signature in Psoriasis

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-, IL-1, 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.