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GSK805 (GSK-805) is a novel, potent, and orally bioavailable RORγt inhibitor with the potential to be used for autoimmune encephalomyelitis (EAE). It inhibits RORγγ with pIC50 of 8.4 and >8.2 for RORγ FRET assay and Th17 assay. Structure-activity relationship exploration on the biaryl moiety led to discovery of potent RORγt inhibitors with good oral bioavailability and CNS penetration. GSK805 demonstrated excellent in vivo efficacy in EAE mice dose dependently with once daily oral administration.
| Targets |
Retinoid-related orphan receptor gamma t (RORγt) [2]
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|---|---|
| ln Vitro |
Th17 cell responses are inhibited by GSK805 (0.5 μM; 4 d) [2]. Assay for cell differentiation [2]
1. Suppression of Th17 cell differentiation: Naïve CD4⁺ T cells were activated with anti-CD3 and anti-CD28 antibodies under Th17 cell-polarizing conditions. GSK805 was added at a concentration of 0.5 μM, with TMP778 (2.5 μM) and DMSO as controls. After 4 days of culture, intracellular cytokine staining was performed to detect the production of IL-17 and IFNγ. The results showed that GSK805 significantly inhibited IL-17 production by Th17 cells, which was representative of 3 independent experiments [2] |
| ln Vivo |
Mice with experimental autoimmune encephalomyelitis (EAE) respond better to GSK805 (10 mg/kg) administered orally once daily for 35 days [2]. In EAE mice, GSK805 (30 mg/kg; once oral) can suppress the Th17 cell response [2].
1. Efficacy in experimental autoimmune encephalomyelitis (EAE) mice: C57BL/6 mice were immunized with MOG35-55 peptide plus complete Freund's adjuvant (CFA) to induce EAE. GSK805 was administered orally at a dose of 10 mg/kg once daily starting from day 0. Daily evaluation of EAE clinical signs showed that GSK805 significantly ameliorated the severity of EAE compared with the control group (p<0.01 by repeated ANOVA test) [2] 2. Inhibition of IL-17 production in CNS-infiltrating cells: EAE-induced mice were treated with GSK805 at a dose of 30 mg/kg. On day 14 after EAE induction, mononuclear cells infiltrating the central nervous system (CNS) were isolated from the brains and spinal cords. Intracellular cytokine staining revealed that GSK805 significantly reduced the production of IL-17 by CNS-infiltrating CD4⁺ T cells (p<0.001) [2] 3. Modulation of Th17 cell transcriptional network: GSK805 regulated the RORγt-dependent transcriptional network in Th17 cells, which was reflected by the altered expression of genes in clusters #1-#5 related to Th17 cell function, consistent with the regulatory effect on RORγt-mediated transcription [2] |
| Cell Assay |
Cell differentiation assay[2]
Cell Types: CD4+ T cells Tested Concentrations: 0.5 μM Incubation Duration: 4 days Experimental Results: Inhibition of IL-17 production during Th17 cell differentiation. 1. Th17 cell differentiation and cytokine production assay: Naïve CD4⁺ T cells were isolated and seeded in culture systems. The cells were activated with anti-CD3 and anti-CD28 antibodies under Th17 cell-polarizing conditions. GSK805 was added to the culture at a final concentration of 0.5 μM, with DMSO as the vehicle control and TMP778 (2.5 μM) as a positive control. The cells were cultured for 4 days, then harvested and fixed. After permeabilization, the cells were stained with specific antibodies against IL-17 and IFNγ. Flow cytometry was used to detect the expression levels of these cytokines in CD4⁺ T cells, and the percentage of cytokine-producing cells was analyzed [2] 2. CNS-infiltrating cell cytokine detection assay: On day 14 after EAE induction, mice treated with GSK805 (30 mg/kg) were euthanized. Brains and spinal cords were collected and homogenized to isolate mononuclear cells. The isolated cells were treated with cell stimulation cocktail, fixed, permeabilized, and stained with anti-CD4, anti-IL-17, and anti-IFNγ antibodies. Flow cytometry was performed to quantify the production of IL-17 and IFNγ in CNS-infiltrating CD4⁺ T cells [2] |
| Animal Protocol |
Animal/Disease Models: Use MOG35-55 plus CFA to immunize C57BL/6 mice [2]
Doses: 10 mg/kg Route of Administration: po (oral gavage); 10 mg/kg, one time/day; Last for 35 days Experimental Results: Effectively improved EAE in mice severity. Animal/Disease Models: C57BL/6 mice with EAE [2] Doses: 30 mg/kg Route of Administration: po (oral gavage); 30 mg/kg Primary Experimental Results: IFN-γ-IL-17+ and IFN in EAE mice -γ+IL-17+ T cells diminished but did not change the frequency of TNF-α+ T cells. 1. EAE mouse model establishment: Female C57BL/6 mice were used for the experiment. The mice were immunized with MOG35-55 peptide emulsified in complete Freund's adjuvant (CFA) to induce experimental autoimmune encephalomyelitis [2] 2. Drug administration: GSK805 was administered to EAE-induced mice via oral gavage. For the efficacy evaluation of EAE severity, the drug dose was 10 mg/kg, administered once daily starting from day 0 after immunization (n=8). For the detection of CNS-infiltrating cell cytokines, the drug dose was 30 mg/kg, with the same administration route and frequency [2] 3. Clinical scoring and sample collection: Mice were evaluated daily for clinical signs of EAE using a standard scoring system. On day 14 after EAE induction, mice in the 30 mg/kg GSK805 treatment group were euthanized. Brains and spinal cords were dissected to isolate mononuclear infiltrating cells for subsequent cytokine detection [2] |
| References | |
| Additional Infomation |
GSK805 is an orally effective RORγt inhibitor that can cross the blood-brain barrier. GSK805 inhibits the differentiation of RORγt and Th17 cells and suppresses the function of Th17 cells. GSK805 can be used in immunological research.
1. Mechanism of Action: GSK805 is a small molecule RORγt antagonist that inhibits the transcriptional network of Th17 cells. RORγt is a key transcriptional regulator of Th17 cell differentiation and function, and GSK805 can inhibit pathogenic Th17 cell responses by regulating RORγt-dependent gene expression [2]. 2. Therapeutic potential: GSK805 showed therapeutic effects in EAE (a mouse model of multiple sclerosis), indicating its potential to treat Th17 cell-mediated autoimmune diseases such as multiple sclerosis [2]. 3. Activity comparison: In in vitro Th17 cell differentiation experiments, GSK805 (0.5 μM) showed potent inhibitory activity against IL-17 production, comparable to the known RORγt inhibitor TMP778 (2.5 μM) [2]. |
| Molecular Formula |
C23H18CL2F3NO4S
|
|---|---|
| Molecular Weight |
532.3595
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| Exact Mass |
531.028
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| Elemental Analysis |
C, 51.89; H, 3.41; Cl, 13.32; F, 10.71; N, 2.63; O, 12.02; S, 6.02
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| CAS # |
1426802-50-7
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| PubChem CID |
71285927
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
617.1±55.0 °C at 760 mmHg
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| Flash Point |
327.0±31.5 °C
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| Vapour Pressure |
0.0±1.8 mmHg at 25°C
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| Index of Refraction |
1.581
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| LogP |
5.41
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
34
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| Complexity |
772
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C([H])=C(C([H])=C(C=1C1=C([H])C([H])=C([H])C([H])=C1OC(F)(F)F)Cl)N([H])C(C([H])([H])C1C([H])=C([H])C(=C([H])C=1[H])S(C([H])([H])C([H])([H])[H])(=O)=O)=O
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| InChi Key |
CEICQMBWAQAIQX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H18Cl2F3NO4S/c1-2-34(31,32)16-9-7-14(8-10-16)11-21(30)29-15-12-18(24)22(19(25)13-15)17-5-3-4-6-20(17)33-23(26,27)28/h3-10,12-13H,2,11H2,1H3,(H,29,30)
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| Chemical Name |
N-[2,6-dichloro-2'-(trifluoromethoxy)[1,1'-biphenyl]-4-yl]-4-(ethylsulfonyl)-benzeneacetamide
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| Synonyms |
RORγt Inverse Agonist II; GSK-805; GSK 805; GSK805; ROR gamma-t-IN-1;
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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 (~187.84 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.70 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.70 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8784 mL | 9.3921 mL | 18.7843 mL | |
| 5 mM | 0.3757 mL | 1.8784 mL | 3.7569 mL | |
| 10 mM | 0.1878 mL | 0.9392 mL | 1.8784 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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