POS0442 GLPG4399: SELECTIVE SIK3 INHIBITION AS A NOVEL MODE OF ACTION FOR THE TREATMENT OF INFLAMMATORY ARTHRITIC DISEASES (PRECLINICAL)

Abstract

BackgroundSalt-inducible kinases (SIKs) is a family of kinases with immunomodulatory function identified using a proprietary adenoviral shRNA knockdown target discovery platform. Moreover, SIK inhibition has previously been shown to have a role in inflammatory signalling.1–3 These findings suggest a therapeutic potential for SIK inhibition in inflammatory indications. A medicinal chemistry effort resulted in the development of a first-in-class, oral, selective SIK3 inhibitor: GLPG4399. This compound may be beneficial in inflammatory diseases such as rheumatoid and psoriatic arthritis which are chronic disorders characterized by impaired joint synovial inflammation.ObjectivesOur research aimed to characterize GLPG4399 and explore its impact in arthritis-relevant inflammatory in vitro phenotypic cell assays, and to evaluate the therapeutic potential of selective SIK3 inhibition in in vivo experimental models of arthritis.MethodsThe selectivity and potency of GLPG4399 was profiled using biochemical and target-based cell assays. The mode of action of selective SIK3 inhibition in inflammation was explored in an in vitro panel of innate (monocytes, macrophages, dendritic cells) and adaptive (B and T lymphocytes) immune phenotypic assays and in a lipopolysaccharide (LPS)-stimulated human whole blood assay by measuring the production of inflammatory cytokines. In vivo target engagement was evaluated in an acute LPS-stimulated cytokine release mouse model by measuring plasma tumour necrosis factor (TNF) α levels. The therapeutic efficacy of GLPG4399 was evaluated in vivo in collagen-induced arthritis (CIA) and IL-23-induced psoriatic arthritis mouse models by assessing disease activity endpoints.ResultsGLPG4399 was shown to be a SIK3 inhibitor with high selectivity against a panel of 370 kinases. The wide effect of SIK3 inhibition on key immune cell types was demonstrated by GLPG4399’s reduction of pro-inflammatory cytokines produced by monocytes, macrophages, dendritic cells, B and T lymphocytes in a panel of in vitro innate and adaptive immune phenotypic assays. The biological activity and target engagement of GLPG4399 was further demonstrated by dose-dependent inhibition of TNFα production in vitro in LPS-stimulated human whole blood and in vivo in the blood of LPS-challenged mice. Oral treatment with GLPG4399 in mice resulted in a significant and dose-dependent improvement of disease activity score in both CIA and the psoriatic arthritis disease model. Moreover, bone erosion in CIA and new bone formation in the psoriatic arthritis disease model were significantly reduced.ConclusionOur preclinical findings demonstrate the strong immunomodulatory effect of SIK3 inhibition in arthritis-relevant inflammatory cell assays and highlight the significant preclinical efficacy of GLPG4399 in two experimental arthritis mouse models. The novel mechanisms of action of GLPG4399 represents a promising approach for the treatment of arthritis.