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

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

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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