Discovery of Clinical Candidate GLPG3970: A Potent and Selective Dual SIK2/SIK3 Inhibitor for the Treatment of Autoimmune and Inflammatory Diseases

The salt-inducible
kinases (SIKs) SIK1, SIK2, and SIK3 belong to
the adenosine monophosphate-activated protein kinase (AMPK) family
of serine/threonine kinases. SIK inhibition represents a new therapeutic
approach modulating pro-inflammatory and immunoregulatory pathways
that holds potential for the treatment of inflammatory diseases. Here,
we describe the identification of GLPG3970 (32), a first-in-class
dual SIK2/SIK3 inhibitor with selectivity against SIK1 (IC50 of 282.8 nM on SIK1, 7.8 nM on SIK2 and 3.8 nM on SIK3). We outline
efforts made to increase selectivity against SIK1 and improve CYP
time-dependent inhibition properties through the structure–activity
relationship. The dual activity of 32 in modulating the
pro-inflammatory cytokine TNFα and the immunoregulatory cytokine
IL-10 is demonstrated in vitro in human primary myeloid
cells and human whole blood, and in vivo in mice
stimulated with lipopolysaccharide. Compound 32 shows
dose-dependent activity in disease-relevant mouse pharmacological
models.