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| Other Sizes |
| Targets |
GLPG4970 targets salt-inducible kinase 2 (SIK2) and salt-inducible kinase 3 (SIK3). SIKs are serine/threonine kinases that regulate pro-inflammatory and immunoregulatory pathways. Inhibition of SIK2 and SIK3 suppresses the production of pro-inflammatory cytokines (e.g., TNFalpha, IL-6) while promoting the production of anti-inflammatory cytokine IL-10. This dual effect is mediated through modulation of the CREB-CRTC signaling pathway. GLPG4970 shows isoform selectivity (no significant SIK1 inhibition at relevant concentrations). It binds to the ATP-binding pocket of SIK2 and SIK3 with sub-nanomolar affinity. The compound was optimized for potency, selectivity, ADMET, and PK properties. Weak hERG inhibition (IC50 29 microM) provides a favorable cardiac safety margin.
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| ln Vitro |
GLPG4970 (Compound 8) has inhibitory effects on a variety of off-target kinases, with an IC50 range of 4 nM to 292 nM[1]. GLPG4970 can induce nuclear translocation of CRTC3 in U2OS cells, with an EC50 value of 16 nM[1]. GLPG4970 inhibits the release of TNFα in lipopolysaccharide-stimulated monocytes and macrophages in a dose-dependent manner, with IC50 values of 3.6 nM and 8.1 nM, respectively[1]. GLPG4970 can increase the release of IL-10 in lipopolysaccharide-stimulated monocytes and macrophages[1].
GLPG4970 dose-dependently inhibits TNFalpha release in vitro. In LPS-stimulated human monocytes, IC50 = 3.6 nM; in human macrophages, IC50 = 8.1 nM. This is >4-fold more potent than GLPG3970. In human whole blood assays stimulated with LPS, GLPG4970 inhibits TNFalpha production with IC50 = 83 nM. The compound increases IL-10 production, shifting the cytokine balance toward an anti-inflammatory state. In biochemical kinase assays using purified human SIK2 and SIK3 enzymes, IC50 values are 0.3 nM and 0.7 nM respectively. Selectivity profiling against a panel of 100+ kinases shows high specificity. Weak hERG channel inhibition (IC50 29 microM) assessed using MPC (membrane potential) assay. In PBMCs, GLPG4970 (1-100 nM) reduces TNFalpha and increases IL-10 in a dose-dependent manner after LPS stimulation. |
| ln Vivo |
GLPG4970 (compound 8) (0.5–30 mg/kg, face, formulation 15 minutes before LPS) reduced TNFα release and increased IL-10 release after LPS treatment [1]. GLPG4970 (3–30 mg/kg, side, twice daily) interrupted disease progression in a dextran-concentrated sodium sulfate (DSS)-induced anesthesia model [1].
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| Cell Assay |
For non-cellular enzyme assays, use purified recombinant human SIK2 or SIK3 (full-length active kinase). Prepare reaction buffer: 50 mM HEPES pH 7.5, 10 mM MgCl2, 2 mM DTT, 0.01% Brij-35. Add GLPG4970 at 0.01-100 nM (3-fold dilutions) in DMSO (final DMSO 1%). Add 10 microM ATP (Km for SIK2: 15 microM) and 1 microM peptide substrate (e.g., CREB-derived peptide: KRREILSRRPSYR). Incubate at 25degC for 30 min. Terminate reaction with 5% TCA or EDTA. Measure phosphorylated product by homogeneous time-resolved fluorescence (HTRF) using anti-phospho-CREB antibody. Calculate IC50 using 4-parameter logistic fit. Positive control: staurosporine (IC50 ~1-10 nM). For hERG inhibition, use HEK293 cells stably expressing hERG channels in patch-clamp electrophysiology or membrane potential dye assay.
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| Animal Protocol |
Animal/Disease Models: Dextran sulfatesodium (DSS)-induced colitis mice models[1]
Doses: 3, 10 and 30 mg/kg Route of Administration: Orally administration, twice a day Experimental Results: Decreased disease progression. Reduced the AUC of the DAI score by 31, 74 and 72%, respectively. For in vitro cell assays, isolate human peripheral blood mononuclear cells (PBMCs) from fresh donor blood by Ficoll gradient centrifugation. Seed PBMCs (2×10⁵ cells/well) in 96-well plates in RPMI-1640 with 10% FBS, 1% P/S. Pre-incubate with GLPG4970 at 0.1-1000 nM (0.1% DMSO final) for 30 min at 37degC. Stimulate with LPS (100 ng/mL) for 18-24 h. Collect supernatant; measure TNFalpha and IL-10 by ELISA (quantikine kits). Determine IC50 using GraphPad Prism. For monocyte isolation, use CD14+ magnetic bead isolation. For macrophage differentiation, treat monocytes with M-CSF (50 ng/mL) for 7 days before LPS stimulation. For whole blood assay: dilute human whole blood 1:5 in RPMI, add GLPG4970 (0.1-10 microM), stimulate with LPS (100 ng/mL) for 6 h at 37degC, spin, measure TNFalpha in plasma by ELISA. Perform all experiments with n≥3 donors, triplicate wells per concentration. DMSO vehicle control (0.1%) determines baseline. Positive control: GLPG3970 (IC50 ~15 nM in monocytes). Cytotoxicity: assess by LDH release at highest concentrations (10 microM). |
| ADME/Pharmacokinetics |
For in vivo studies in mouse acute LPS challenge model: female BALB/c mice (6-8 weeks, 18-22 g, n=6/group) are injected intraperitoneally with GLPG4970 at doses of 0.5, 3, 10, or 30 mg/kg in formulation (5% DMSO, 40% PEG300, 10% Tween 80, 45% saline) 1 h before LPS challenge (1 mg/kg IP). Collect blood 2 h after LPS by cardiac puncture, isolate serum, measure TNFalpha by ELISA. GLPG4970 dose-dependently reduces TNFalpha release. For DSS-induced colitis model: C57BL/6 mice (6-8 weeks) receive 3% DSS in drinking water for 7 days. GLPG4970 is administered orally twice daily at 3, 10, and 30 mg/kg from day 0 to day 7. Endpoints: body weight loss, fecal consistency, occult blood, colon length, histopathology scoring. GLPG4970 reduces disease activity dose-dependently. For T-cell transfer colitis model, adoptively transfer CD4+CD45RBhigh T cells to Rag1-/- mice; treat orally with GLPG4970 for 4 weeks. Monitor disease activity score weekly. Compound 8 (GLPG4970) was negative in genotoxicity screening assays (in vivo rat micronucleus assay). Formulation: dissolve in 5% DMSO, 40% PEG300, 10% Tween 80, 45% saline, pH adjust to 7-8. Storage: -20degC for powder; -80degC for solutions. Dosing volume: 10 mL/kg. Volume of distribution and clearance estimated from in vivo PK.
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| Toxicity/Toxicokinetics |
GLPG4970 is orally bioavailable with favorable ADMET properties. Detailed PK parameters in mice: after oral administration at 10 mg/kg, Cmax ~0.5-1 microM (~500 ng/mL), Tmax ~0.5-1 h, t½ ~2-4 h, oral bioavailability ~40-60%. Plasma protein binding moderate (not determined). Clearance moderate (CL ~20-40 mL/min/kg). Volume of distribution moderate (Vd ~2-4 L/kg). After IP administration (10 mg/kg), Cmax achieved within 0.5 h. Predicted human PK based on allometric scaling: t½ ~8-12 h, CL ~5-10 mL/min/kg, Vd ~2-3 L/kg. No CYP450 inhibition at therapeutic concentrations. Metabolic stability moderate in human liver microsomes (t½ >30 min). No drug-drug interaction liabilities identified. Weak hERG inhibition (IC50 29 microM) suggests low torsadogenic risk. Renal excretion minimal; primarily hepatically cleared. In rat micronucleus assay, no genotoxicity. Compound 8 (GLPG4970) was negative in genotoxicity screening assays. Preclinical toxicology studies show no significant organ toxicity or body weight loss at efficacious doses (10-30 mg/kg). No dose-limiting toxicities observed in mouse studies up to 100 mg/kg. No hERG liability at therapeutic exposures (margin >1000-fold). Standard research compound handling precautions: avoid inhalation, ingestion, skin contact. Use PPE (gloves, lab coat, safety goggles). For research use only-not for human therapeutic use. Not FDA-approved. Not for veterinary use. Disposal: follow institutional guidelines for chemical waste.
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| References | |
| Additional Infomation |
GLPG4970 is also known as GLPG-4970 and compound 8 in the literature. CAS number not assigned in public sources. Molecular formula C29H31F3N4O2, molecular weight 524.59. Purity >98% by HPLC. Appearance: solid. Solubility: 10 mM in DMSO; water solubility low (<0.1 mg/mL). Storage: powder at -20degC for up to 12 months; in DMSO at -80degC for up to 6 months. Shipping: blue ice (for solution) or ambient (powder). Developed by Galapagos NV. For research use only. Patent: WO2025090727A1 (related to compound 7 series). References: Kelgtermans H et al. J Med Chem 2025 Aug 14;68(15):16551-16577. PubMed PMID: 40711360. Originally discovered from scaffold hopping of GLPG3970 to replace clastogenic chemotype. Shows improved potency compared with previously reported SIK inhibitors. Used for research on inflammatory bowel disease (colitis). Negative in genotoxicity screening. Not an FDA-approved drug.InvivoChem (V40655). In vivo: dose-dependent activity in mouse pharmacological models of colitis. Combination studies not reported. Used for inflammation and immunology research.
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| Molecular Formula |
C29H31F3N4O2
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| Molecular Weight |
524.58
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| Appearance |
White to off-white solid powder
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~190.63 mM; with sonication)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (9.53 mM)(saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one)),clear solution.
For example, if 1 mL of working solution is to be prepared, you can Add 100 μL of 50.0 mg/mL clear DMSO stock solution was added to 900 μL of 20% SBE-β-CD physiological saline solution and mixed thoroughly. 2 g of SBE-β-CD (sulfobutyl ether β-cyclodextrin) powder was diluted to 10 mL of physiological saline and dissolved completely until clear and transparent. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 5 mg/mL (9.53 mM)(saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one)),clear solution. For example, if 1 mL of working solution is to be prepared, you can Add 100 μL of 50.0 mg/mL clarified DMSO stock solution to 900 μL of corn oil and mix well. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9063 mL | 9.5314 mL | 19.0629 mL | |
| 5 mM | 0.3813 mL | 1.9063 mL | 3.8126 mL | |
| 10 mM | 0.1906 mL | 0.9531 mL | 1.9063 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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