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Optimization of Selectivity and Pharmacokinetic Properties of Salt-Inducible Kinase Inhibitors that Led to the Discovery of Pan-SIK Inhibitor GLPG3312.
Temal-Laib, Taouès; Peixoto, Christophe; Desroy, Nicolas; De Lemos, Elsa; Bonnaterre, Florence; Bienvenu, Natacha; Picolet, Olivier; Sartori, Eric; Bucher, Denis; López-Ramos, Miriam; Roca Magadán, Carlos; Laenen, Wendy; Flower, Thomas; Mollat, Patrick; Bugaud, Olivier; Touitou, Robert; Pereira Fernandes, Anna; Lavazais, Stephanie; Monjardet, Alain; Borgonovi, Monica; Gosmini, Romain; Brys, Reginald; Amantini, David; De Vos, Steve; Andrews, Martin.
Affiliation
  • Temal-Laib T; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • Peixoto C; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • Desroy N; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • De Lemos E; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • Bonnaterre F; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • Bienvenu N; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • Picolet O; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • Sartori E; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • Bucher D; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • López-Ramos M; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • Roca Magadán C; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • Laenen W; Galapagos NV, Generaal De Wittelaan L11, A3, 2800 Mechelen, Belgium.
  • Flower T; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • Mollat P; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • Bugaud O; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • Touitou R; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • Pereira Fernandes A; Galapagos NV, Generaal De Wittelaan L11, A3, 2800 Mechelen, Belgium.
  • Lavazais S; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • Monjardet A; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • Borgonovi M; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • Gosmini R; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • Brys R; Galapagos NV, Generaal De Wittelaan L11, A3, 2800 Mechelen, Belgium.
  • Amantini D; Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • De Vos S; Galapagos NV, Generaal De Wittelaan L11, A3, 2800 Mechelen, Belgium.
  • Andrews M; Galapagos NV, Generaal De Wittelaan L11, A3, 2800 Mechelen, Belgium.
J Med Chem ; 67(1): 380-401, 2024 01 11.
Article in En | MEDLINE | ID: mdl-38147525
ABSTRACT
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.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Protein Serine-Threonine Kinases / AMP-Activated Protein Kinases Limits: Animals / Humans Language: En Journal: J Med Chem Year: 2024 Document type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Protein Serine-Threonine Kinases / AMP-Activated Protein Kinases Limits: Animals / Humans Language: En Journal: J Med Chem Year: 2024 Document type: Article