Structure-Activity Relationship Guided Scaffold Hopping Resulted in the Identification of GLPG4970, a Highly Potent Dual SIK2/SIK3 Inhibitor

  • J Med Chem. 2025 Aug 14;68(15):16551-16577. doi: 10.1021/acs.jmedchem.5c01401.
Hans Kelgtermans  1 ,  Maxim De Wachter  1 ,  Stijn Heyndrickx  1 ,  Sandy El Bkassiny  1 ,  Tatiana Lacarriere  1 ,  Chris Laruelle  1 ,  Jörg Heiermann  2 ,  Wendy van Bruggen  2 ,  Katarzyna Drabik  2 ,  Denis Bucher  3 ,  Thomas Coudrat  3 ,  Emilie Jigorel  3 ,  Kenneth Goossens  1 ,  Michael Drennan  1 ,  Martine Vrints  1 ,  Maarten Verbeeck  1 ,  Bas Housmans  1 ,  Damien Ronsse  1 ,  David Moreno-Delgado  1 ,  Vahid Nassiri  4 ,  Mia Jans  1 ,  Maarten Gees  1 ,  Emanuelle Wakselman  3 ,  Line Oste  1 ,  Monica Borgonovi  3 ,  Elena Borregán-Ochando  1 ,  Vladyslav Sushko  1 ,  Alain Monjardet  3 ,  Camille Dusserre  3 ,  Frederique Van Acker  5 ,  Anouk Blaauw  5 ,  Stephanie Lavazais  3 ,  Catherine Jagerschmidt  3 ,  Didier Merciris  3 ,  Michael Török-Schafroth  6 ,  Christian A Seemayer  6 ,  Katja Conrath  1 ,  Fabrice A Kolb  6 ,  Pierre Raboisson  1 ,  Reginald Brys  1 ,  David Amantini  3 ,  Romain Gosmini  3 ,  Alexis Denis  3 ,  Juan-Miguel Jimenez  1 ,  Steve De Vos  1 ,  Nicolas Desroy  3
Affiliations
  • 1. Galapagos NV, 2800 Mechelen, Belgium.
  • 2. Symeres B.V., 6546 BB Nijmegen, The Netherlands.
  • 3. Galapagos SASU, 93230 Romainville, France.
  • 4. Open Analytics, 2600 Antwerp, Belgium.
  • 5. Galapagos B.V., 2342 BH Oegstgeest, The Netherlands.
  • 6. Galapagos GmbH, 4051 Basel, Switzerland.
PMID: 40711360 DOI: 10.1021/acs.jmedchem.5c01401
Abstract

Inhibition of salt-inducible Kinases (SIKs) SIK1, SIK2, and SIK3 represents a new potential therapeutic approach for autoimmune and inflammatory disease treatment via modulation of pro-inflammatory and immunoregulatory pathways, particularly inhibition of SIK2 and SIK3. After discovering a new chemotype for SIK inhibition, further optimization of potency, selectivity, ADMET and PK properties resulted in a 1,6-naphtyridine containing molecule GLPG4876 (7). However, 7 was clastogenic when examined in vivo in rat micronucleus assays, preventing further development. Overlay of 7 with GLPG3970 (6) within the SIK3 protein structure inspired the design of pyridine derivatives, leading to the identification of GLPG4970 (8). Compound 8 was negative in genotoxicity screening assays and demonstrated potent SIK2/SIK3 inhibition, for which isoform selectivity was determined in a cellular context. Compound 8 displayed improved potency compared with previously reported SIK inhibitors in biochemical and phenotypic cellular assays, and showed dose-dependent activity in disease relevant mouse pharmacological models of Colitis.

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