J Med Chem. 2024 Mar 29.
Christophe Peixoto,
Agnes Joncour,
Taouès Temal-Laib,
Amynata Tirera,
Aurélie Dos Santos,
Hélène Jary,
Denis Bucher,
Wendy Laenen,
Anna Pereira Fernandes,
Stephanie Lavazais,
Carole Delachaume,
Didier Merciris,
Corinne Saccomani,
Michael Drennan,
Miriam López-Ramos,
Emanuelle Wakselman,
Sonia Dupont,
Monica Borgonovi,
Carlos Roca Magadan,
Alain Monjardet,
Reginald Brys,
Steve De Vos,
Martin Andrews,
Juan-Miguel Jimenez,
David Amantini,
Nicolas Desroy.
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.