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Purity: ≥98%
SAR-20347 is a novel and potent small molecule inhibitor with specificity for JAK1 and tyrosine kinase 2 (TYK2) over other JAK family members. In cellular assays, SAR-20347 dose dependently (1 nM-10 μM) inhibited JAK1- and/or TYK2-dependent signaling from the IL-12/IL-23, IL-22, and IFN-α receptors. In vivo, TYK2 mutant mice or treatment of wild-type mice with SAR-20347 significantly reduced IL-12-induced IFN-γ production and IL-22-dependent serum amyloid A to similar extents, indicating that, in these models, SAR-20347 is probably acting through inhibition of TYK2. In an imiquimod-induced psoriasis model, the administration of SAR-20347 led to a striking decrease in disease pathology, including reduced activation of keratinocytes and proinflammatory cytokine levels compared with both TYK2 mutant mice and wild-type controls. Taken together, these data indicate that targeting both JAK1- and TYK2-mediated cytokine signaling is more effective than TYK2 inhibition alone in reducing psoriasis pathogenesis.
| Targets |
SAR-20347 acts as a small molecule inhibitor with specificity for tyrosine kinase 2 (TYK2) and Janus Kinase 1 (JAK1), and has lower specificity for other JAK family members (JAK2, JAK3) [1]
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| ln Vitro |
When NK-92 cells are stimulated with IL-12, SAR-20347 potently suppresses the TYK2-dependent event of STAT4 phosphorylation, which is mediated by IL-12, with an IC50 of 126 nM. The selectivity of SAR-20347 is TYK2>JAK1>JAK2>JAK3. When SAR-20347 and IL-12 were added to the culture medium, the synthesis of IFN-γ was dose-dependently inhibited in the cells that produced no detectable amount of the protein. The generation of secreted embryonic alkaline phosphatase (SEAP) is inhibited dose-dependently by SAR-20347, with the highest inhibitory impact observed in these trials at 5 μM [1].
1. SAR-20347 dose-dependently (1 nM-10 μM) inhibited JAK1- and/or TYK2-dependent signaling from the IL-12/IL-23, IL-22, and IFN-α receptors in cellular assays [1] 2. In human peripheral blood mononuclear cells (PBMCs), SAR-20347 inhibited IL-12 (10 ng/mL)-induced IFN-γ production in the supernatant in a concentration-dependent manner after 24 hours of incubation [1] 3. In HEK-BLUE IFN-α/β reporter cells, SAR-20347 reduced IFN-α (200 U)-induced secreted embryonic alkaline phosphatase (SEAP) levels in a concentration-dependent manner after 24 hours of treatment [1] 4. In HT-29 cells, SAR-20347 inhibited IL-22 (10 ng/mL)-induced STAT3 phosphorylation (pSTAT3) levels in a concentration-dependent manner, as assessed by flow cytometry [1] 5. SAR-20347 (1 μM) altered the in vitro development of mouse T helper subsets: it reduced the proportion of Th1 and Th17 cells, and had a significant effect on CD4+ T cell proliferation compared with the no-inhibitor control [1] |
| ln Vivo |
SAR-20347 suppresses TYK2 signaling in vivo, as demonstrated by its 91% inhibition of IFN-γ production in serum at 60 mg/kg when compared to mice administered with a vehicle. In line with gene expression data, SAR-20347 therapy dramatically decreased IL-17 production as determined by mean signal intensity [1].
1. In C57BL/6 mice pretreated with SAR-20347 (50 mg/kg), IL-22-induced serum amyloid A (SAA) levels were significantly reduced at 6 hours post-IL-22 injection (10 μg, i.p.), to a similar extent as in TYK2 mutant mice [1] 2. In an imiquimod-induced psoriasis-like dermatitis model, oral administration of SAR-20347 (50 mg/kg, twice daily) to wild-type (WT) mice led to a striking decrease in disease pathology, including reduced clinical scores for redness and scaling, lower epidermal thickness (assessed by keratinocyte count), and decreased Ki67-positive cell proliferation in the epidermis compared with WT vehicle-treated mice and TYK2 mutant mice [1] 3. SAR-20347 treatment significantly reduced the mRNA expression of proinflammatory cytokines (IL-22, IL-23, IL-17, IL-6, IL-20, TNF) and antimicrobial peptides (S100A8, S100A9, Defensin β1) in the skin of imiquimod-treated mice, with a more pronounced effect than TYK2 mutation alone [1] 4. In the imiquimod model, SAR-20347 treatment also decreased the signal intensity of IL-17 and Vγ3 in skin samples, indicating reduced activation of γδ T cells [1] |
| Enzyme Assay |
A biochemical time-resolved fluorescence resonance energy transfer (TR-FRET) assay was performed to evaluate the kinase specificity of SAR-20347: the assay detected the inhibitory activity of SAR-20347 on TYK2, JAK1, JAK2, and JAK3 at different concentrations, and the resulting inhibition curves were used to compare the specificity of SAR-20347 for these JAK family members [1]
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| Cell Assay |
1. For the PBMC assay: PBMCs were incubated with serial concentrations of SAR-20347 or DMSO, then stimulated with 10 ng/mL human IL-22 for 24 hours; the concentration of IFN-γ in the cell supernatant was measured and compared with DMSO-treated control cells [1]
2. For the HEK-BLUE IFN-α/β reporter cell assay: HEK-BLUE cells were incubated with SAR-20347 and stimulated with 200 U IFN-α for 24 hours; SEAP levels in the supernatant were detected and compared with DMSO-treated control cells [1] 3. For the HT-29 cell IL-22 signaling assay: HT-29 cells were pretreated with SAR-20347 or DMSO for 20 minutes, then incubated with 10 ng/mL human IL-22 for 15 minutes; pSTAT3 levels were assessed by flow cytometry, and the change in mean fluorescence intensity was plotted relative to DMSO controls [1] 4. For the mouse T helper subset differentiation assay: CD4+ T cells were cultured with 1 μM SAR-20347 or tofacitinib in the presence of Th1, Th2, Th17, or iTreg lineage-driving cytokines for 4 days; cells were stimulated, and intracellular staining for relevant cytokines was performed for flow cytometric analysis [1] 5. For the CD4+ T cell proliferation assay: CD4+ T cells were cultured in anti-CD28/anti-TCR-coated plates with serial concentrations of SAR-20347 for 4 days; cell proliferation was evaluated and compared with the 0 μM inhibitor control (DMSO) [1] |
| Animal Protocol |
1. For the IL-22-induced SAA assay: C57BL/6 mice were pretreated with vehicle (N=6) or 50 mg/kg SAR-20347 (N=6) via oral administration; then the mice were injected intraperitoneally (i.p.) with 10 μg mouse IL-22 or vehicle/PBS (N=4), and serum SAA levels were measured 6 hours post-injection [1]
2. For the imiquimod-induced psoriasis-like dermatitis model: WT mice were treated with vehicle (N=6) or 50 mg/kg SAR-20347 (N=5) via oral administration twice daily, and TYK2 mutant mice were treated with vehicle only (N=6); all mice were topically treated with imiquimod daily for 6 days. Clinical scores for redness and scaling were assessed, skin samples were collected for H&E staining (to evaluate epidermal thickness and disease severity) and Ki67 staining (to measure cell proliferation), and skin RNA was extracted for qPCR analysis of cytokine and antimicrobial peptide expression [1] |
| Toxicity/Toxicokinetics |
The literature does not mention in vitro and in vivo toxicity/side effects information of SAR-20347, such as median lethal dose, hepatotoxicity and nephrotoxicity, drug interactions and plasma protein binding rate [1].
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| References | |
| Additional Infomation |
1. SAR-20347 is a small molecule inhibitor used to treat psoriasis. Psoriasis is a chronic autoimmune skin disease characterized by abnormal proliferation of keratinocytes and release of pro-inflammatory cytokines[1]. 2. The mechanism of action of SAR-20347 is to block the cytokine signaling pathways mediated by JAK1 and TYK2 (IL-22, IL-23/IL-17 axis), thereby inhibiting the activation of keratinocytes and the production of pro-inflammatory cytokines and antimicrobial peptides in the skin[1]. 3. Compared with inhibiting TYK2 alone, using SAR-20347 to simultaneously target the cytokine signaling pathways mediated by JAK1 and TYK2 can more effectively alleviate the pathogenesis of psoriasis[1].
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| Molecular Formula |
C21H18CLFN4O4
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|---|---|
| Molecular Weight |
444.8434
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| Exact Mass |
444.1
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| CAS # |
1450881-55-6
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| Related CAS # |
1450881-55-6; 1450881-50-6
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| PubChem CID |
71727668
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
698.3±65.0 °C at 760 mmHg
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| Flash Point |
376.1±34.3 °C
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| Vapour Pressure |
0.0±2.2 mmHg at 25°C
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| Index of Refraction |
1.644
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| LogP |
0.22
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
31
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| Complexity |
645
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
HEDPDFHTQKEORT-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H18ClFN4O4/c22-14-2-1-3-15(23)16(14)19-26-17(18(24)28)20(31-19)25-13-6-4-12(5-7-13)21(29)27-8-10-30-11-9-27/h1-7,25H,8-11H2,(H2,24,28)
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| Chemical Name |
2-(2-Chloro-6-fluorophenyl)-5-[[4-(4-morpholinylcarbonyl)phenyl]amino]-4-oxazolecarboxamide
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| Synonyms |
SAR-20347; SAR 20347; SAR20347
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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 (~224.80 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.62 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 (5.62 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 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2480 mL | 11.2400 mL | 22.4800 mL | |
| 5 mM | 0.4496 mL | 2.2480 mL | 4.4960 mL | |
| 10 mM | 0.2248 mL | 1.1240 mL | 2.2480 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.
SAR20347 altersin vitrodevelopment of mouse T helper subsets.J Immunol.2014 Oct1;193(7):3278-87. |
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 SAR-20347 inhibits TYK2- and JAK1-mediated IL-12 and IFN-α signaling.J Immunol.2014 Oct1;193(7):3278-87. |
 SAR-20347 reduces imiquimod-induced inflammation and keratinocyte cell numbers.J Immunol.2014 Oct1;193(7):3278-87. |
 SAR-20347 reduces imiquimod-induced inflammation and antimicrobial peptide production.J Immunol.2014 Oct1;193(7):3278-87. |
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 SAR-20347 treatment and TYK2 mutant mice show reduced IL-17 and Vγ3.J Immunol.2014 Oct1;193(7):3278-87. |
 Proposed mechanism of action of SAR-20347 in ameliorating psoriasis-like symptoms.J Immunol.2014 Oct1;193(7):3278-87. |
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