posted on 2023-12-26, 19:15authored byTaouès Temal-Laib, Christophe Peixoto, Nicolas Desroy, Elsa De Lemos, Florence Bonnaterre, Natacha Bienvenu, Olivier Picolet, Eric Sartori, Denis Bucher, Miriam López-Ramos, Carlos Roca Magadán, Wendy Laenen, Thomas Flower, Patrick Mollat, Olivier Bugaud, Robert Touitou, Anna Pereira Fernandes, Stephanie Lavazais, Alain Monjardet, Monica Borgonovi, Romain Gosmini, Reginald Brys, David Amantini, Steve De Vos, Martin Andrews
Salt-inducible kinases
(SIKs) SIK1, SIK2, and SIK3 are serine/threonine
kinases and form a subfamily of the protein kinase AMP-activated protein
kinase (AMPK) family. Inhibition of SIKs in stimulated innate immune
cells and mouse models has been associated with a dual mechanism of
action consisting of a reduction of pro-inflammatory cytokines and
an increase of immunoregulatory cytokine production, suggesting a
therapeutic potential for inflammatory diseases. Following a high-throughput
screening campaign, subsequent hit to lead optimization through synthesis,
structure–activity relationship, kinome selectivity, and pharmacokinetic
investigations led to the discovery of clinical candidate GLPG3312
(compound 28), a potent and selective pan-SIK inhibitor
(IC50: 2.0 nM for SIK1, 0.7 nM for SIK2, and 0.6 nM for
SIK3). Characterization of the first human SIK3 crystal structure
provided an understanding of the binding mode and kinome selectivity
of the chemical series. GLPG3312 demonstrated both anti-inflammatory
and immunoregulatory activities in vitro in human
primary myeloid cells and in vivo in mouse models.