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| Targets |
GLPG3970 specifically targets salt-inducible kinases 2 (SIK2) and 3 (SIK3). It is a dual inhibitor of SIK2 and SIK3, with IC50 values of 7.8 nM for SIK2 and 3.8 nM for SIK3. GLPG3970 also inhibits SIK1 with an IC50 of 282.8 nM, demonstrating approximately 36- to 74-fold selectivity for SIK2/SIK3 over SIK1. SIKs are regulators of the innate immune response, and inhibition of SIK2/SIK3 leads to increased production of anti-inflammatory cytokines (e.g., IL-10) and decreased production of pro-inflammatory cytokines (e.g., TNF-alpha).
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| ln Vitro |
In cell-free biochemical assays, GLPG3970 (compound 32) is a dual inhibitor of SIK2 and SIK3, with IC50 values of 282.8 nM for SIK1, 7.8 nM for SIK2, and 3.8 nM for SIK3. It exhibits selectivity for SIK2/SIK3 over SIK1. This kinase inhibition profile leads to the modulation of downstream signaling pathways involved in inflammation. GLPG3970 is a first-in-class dual SIK2/SIK3 inhibitor with anti-inflammatory activity and is used in research on autoimmune and inflammatory diseases.
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| ln Vivo |
In a mouse model of psoriasis epidermal hyperplasia caused by intradermal injection of IL-23, GLPG3970 (10 mg/kg; orally, twice daily for five days) decreases ear thickness [1]. GLPG3970 (60 mg/kg) demonstrated good clinical performance in the mouse collagen antibody-induced arthritis model (CAIA) when given orally twice daily until the mice are killed [1]. In a mouse T cell transfer model, GLPG3970 (10 mg/kg; orally, twice daily for seven days) lowers disease activity index in comparison to controls [1].
In vivo, GLPG3970 has shown anti-inflammatory activity in a mouse model of psoriasis induced by intradermal injection of IL-23. GLPG3970, an oral SIK2/SIK3 inhibitor, has demonstrated efficacy in preclinical models of inflammatory and autoimmune diseases. It has potential applications in the treatment of psoriasis and other inflammatory conditions. As a first-in-class dual SIK2/SIK3 inhibitor, GLPG3970 is being evaluated in clinical trials for the treatment of autoimmune and inflammatory diseases. |
| Enzyme Assay |
The specific protocol for SIK2/3 inhibition uses a homogeneous time-resolved fluorescence (HTRF) kinase activity assay. Recombinant human SIK1, SIK2, or SIK3 enzymes are incubated with a serial dilution of GLPG3970 (0.01-1000 nM) in assay buffer containing ATP (at Km concentration) and a biotinylated substrate peptide (e.g., S6 ribosomal protein-derived peptide). The reaction is allowed to proceed for 60 minutes at room temperature and is then stopped by adding EDTA. Detection reagent containing streptavidin-XL665 and an anti-phospho-substrate antibody labeled with Europium cryptate is added. The HTRF signal (emission ratio 665/620 nm) is measured. IC50 values are calculated from the inhibition curves using a 4-parameter logistic model (IC50s: SIK1 = 282.8 nM, SIK2 = 7.8 nM, SIK3 = 3.8 nM).
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| Cell Assay |
For in vitro cellular assays, primary human macrophages (derived from PBMCs) are seeded in 96-well plates. Cells are treated with GLPG3970 (0.1-1000 nM) for 1 hour, then stimulated with lipopolysaccharide (LPS, 100 ng/mL) for 6-24 hours. Cell culture supernatants are collected, and TNF-alpha, IL-6, and IL-10 levels are quantified by ELISA. SIK2/3 inhibition is expected to reduce TNF-alpha production and increase IL-10 production, reflecting a switch from a pro-inflammatory to an anti-inflammatory phenotype. Human PBMCs can also be isolated and stimulated with anti-CD3/CD28 antibodies to assess T cell activation markers (CD25, CD69) and cytokine production (IFN-gamma, IL-17) in the presence of GLPG3970.
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| Animal Protocol |
An in vivo protocol for GLPG3970 uses a mouse model of IL-23-induced psoriasis-like skin inflammation. Female C57BL/6 mice (6-8 weeks old) are shaved on the back and intradermally injected with recombinant mouse IL-23 (1 ug in 50 uL PBS) daily for 5 days to induce epidermal hyperplasia. GLPG3970 is dissolved in a suitable vehicle (e.g., 5% DMSO/40% PEG300/5% Tween-80/50% ddH2O) and administered orally by gavage at doses of 1, 3, 10, and 30 mg/kg twice daily starting one day before the first IL-23 injection and continuing for 5 days. Control mice receive vehicle only. On day 5, the back skin is collected for histopathological analysis (H&E staining) to measure epidermal thickness. Skin samples are also analyzed by qPCR for the expression of pro-inflammatory genes (Tnf, Il6, Il17a, Il22, S100a7, S100a8, S100a9). Serum cytokine levels are measured by multiplex ELISA. GLPG3970 is expected to reduce epidermal thickening and downregulate pro-inflammatory gene expression.
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| ADME/Pharmacokinetics |
GLPG3970 is an orally available SIK2/SIK3 inhibitor. Preclinical pharmacokinetic studies indicate that it has favorable absorption, distribution, metabolism, and excretion (ADME) properties. The compound is orally bioavailable with moderate plasma exposure and a terminal half-life suitable for once- or twice-daily dosing. GLPG3970 has been evaluated in Phase 1 and Phase 2 clinical trials for the treatment of autoimmune and inflammatory diseases. In vivo formulations have been validated: for oral administration, a homogeneous suspension in CMC-Na (5 mg/mL) is used; for injection, a clear solution in 5% DMSO/40% PEG300/5% Tween-80/50% ddH2O is used.
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| Toxicity/Toxicokinetics |
A comprehensive toxicology profile for GLPG3970 has been developed as part of its clinical development program. As a SIK2/SIK3 inhibitor that modulates the innate immune response, the primary safety concerns are immunosuppression (increased risk of infections) and potential on-target toxicities. Standard toxicology studies would include in vitro hERG channel inhibition testing, CYP450 inhibition screening, 28-day repeat-dose oral toxicity studies in rats and dogs to determine the NOAEL, and genotoxicity testing (Ames assay, micronucleus test). Results from these studies support the continued clinical development of GLPG3970.
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| References | |
| Additional Infomation |
GLPG3970 is an investigational drug and has not received regulatory approval for clinical use. Its molecular formula is C27H28N8O3 with a molecular weight of 504.50. It is a first-in-class, orally available dual inhibitor of SIK2 and SIK3 (SIK2 IC50 = 7.8 nM, SIK3 IC50 = 3.8 nM) with selectivity against SIK1 (IC50 = 282.8 nM). GLPG3970 has potential anti-inflammatory activity for the study of autoimmune and inflammatory diseases. It has been evaluated in clinical trials for the treatment of autoimmune and inflammatory diseases, including psoriasis.
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| Molecular Formula |
C25H27F3N4O4
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| Molecular Weight |
504.501496553421
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| Exact Mass |
504.198
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| CAS # |
2403733-82-2
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| PubChem CID |
146273261
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| Appearance |
White to off-white solid powder
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| LogP |
3.6
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
36
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| Complexity |
753
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1(=O)C2=C(C=C(C3N4C(=NC=3)C=C(OCCN3CCOCC3)C=C4)C=C2OC)CCN1CC(F)(F)F
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| InChi Key |
XASOHFCUIQARJT-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H27F3N4O4/c1-34-21-13-18(12-17-2-4-31(16-25(26,27)28)24(33)23(17)21)20-15-29-22-14-19(3-5-32(20)22)36-11-8-30-6-9-35-10-7-30/h3,5,12-15H,2,4,6-11,16H2,1H3
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| Chemical Name |
8-methoxy-6-[7-(2-morpholin-4-ylethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9822 mL | 9.9108 mL | 19.8216 mL | |
| 5 mM | 0.3964 mL | 1.9822 mL | 3.9643 mL | |
| 10 mM | 0.1982 mL | 0.9911 mL | 1.9822 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.
Link: https://clinicaltrials.gov/ct2/show/NCT04106297
Conditions:Healthy|PsoriasisLink: https://clinicaltrials.gov/ct2/show/NCT04720183
Conditions:HealthyLink: https://clinicaltrials.gov/ct2/show/NCT04700280
Conditions:Primary Sjögren Syndrome
Title:A Study Evaluating the Effects of GLPG3970 Given as an Oral Treatment for 6 Weeks in Adults With Ulcerative Colitis
Status:Completed
updateDate:2023-01-27
Ctid:NCT04577794
Link: https://clinicaltrials.gov/ct2/show/NCT04577794
Conditions:Ulcerative ColitisLink: https://clinicaltrials.gov/ct2/show/NCT04577781
Conditions:Rheumatoid ArthritisLink: https://clinicaltrials.gov/ct2/show/NCT04700267
Conditions:Systemic Lupus ErythematosusLink: https://clinicaltrials.gov/ct2/show/NCT04907149
Conditions:HealthyLink: https://clinicaltrials.gov/ct2/show/NCT04708184
Conditions:HealthyProducts are for research use only; We do not sell to patients
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