| Size | Price | Stock | Qty |
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| Targets |
Izencitinib targets the Janus kinase (JAK) family of intracellular tyrosine kinases, which includes JAK1, JAK2, JAK3, and TYK2. JAKs are key mediators of cytokine signaling through the JAK-STAT pathway. By inhibiting JAKs, izencitinib blocks the phosphorylation and activation of signal transducer and activator of transcription (STAT) proteins, thereby reducing the production of inflammatory cytokines. Izencitinib is a pan-JAK inhibitor, meaning it inhibits all four JAK family members. The compound's gut-restricted design limits its systemic exposure, reducing the risk of systemic side effects such as infections and hematologic abnormalities.
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| ln Vitro |
Human vascular epithelial cell lines (pIC50 ≥ 6.7) and peripheral blood mononuclear cells (PBMC) are not phosphorylated STAT in response to cytokines when izencitinib (TD-1473) is administered [1]. A strong JAK1, JAK2, JAK3, and TYK2 domain inhibitor, is izencitinib (TD-1473), which targets human JAK domains (pKi values of 10.0, 10.0, 8.8, and 9.5, respectively) [1].
In vitro, izencitinib demonstrates potent inhibition of human recombinant JAK kinases with pKi values of 10.0, 10.0, 8.8, and 9.5 for JAK1, JAK2, JAK3, and TYK2, respectively. The compound's activity is assessed using biochemical kinase assays measuring the inhibition of JAK-mediated phosphorylation. Izencitinib also inhibits JAK-STAT signaling in cell-based assays, reducing the phosphorylation of STAT proteins and the production of inflammatory cytokines. The compound's gut-restricted properties are assessed by measuring its permeability and efflux in intestinal epithelial cell models. |
| ln Vivo |
Izencitinib (TD-1473, 1 mg/kg BID) retains body weight and lowers occult blood scores in a mouse oxazolone bilayer inflammatory model [1].
In vivo, izencitinib demonstrates anti-inflammatory activity in preclinical models of inflammatory bowel disease. The compound's gut-restricted design is intended to provide local efficacy in the gastrointestinal tract while minimizing systemic exposure. In animal models of colitis, izencitinib reduces inflammation and improves clinical disease activity scores. The compound's gut selectivity is confirmed by measuring drug concentrations in intestinal tissue versus plasma. |
| Enzyme Assay |
Izencitinib's inhibition of JAK kinases is assessed using biochemical kinase assays. Recombinant JAK1, JAK2, JAK3, and TYK2 are incubated with the test compound, ATP, and a peptide substrate; phosphorylation of the substrate is detected using HTRF or luminescence-based methods. IC50 or pKi values are calculated from dose-response curves. Selectivity for JAK family members over other kinases is assessed by screening against a panel of kinases. These assays provide quantitative information on the potency and selectivity of izencitinib.
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| Cell Assay |
Izencitinib is tested on cultured immune cells (e.g., peripheral blood mononuclear cells, T cells) and intestinal epithelial cells. Cells are stimulated with cytokines (e.g., IL-6, IFN-γ) in the presence or absence of izencitinib; STAT phosphorylation is assessed by flow cytometry or Western blot; cytokine production is measured by ELISA; cell proliferation is assessed by thymidine incorporation or CFSE dilution. Intestinal permeability and efflux are assessed using Caco-2 or MDCK cell models. These cell-based assays demonstrate the mechanism of action and gut-restricted properties of izencitinib.
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| Animal Protocol |
Izencitinib is evaluated in animal models of inflammatory bowel disease, including DSS-induced colitis and TNBS-induced colitis models. In these models, izencitinib is administered orally at various doses; disease activity index, colon length, histological inflammation, and inflammatory cytokine levels are assessed. Drug concentrations in plasma and intestinal tissue are measured to confirm gut selectivity. These in vivo studies provide evidence for the efficacy and gut-restricted properties of izencitinib.
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| ADME/Pharmacokinetics |
Pharmacokinetic studies of izencitinib have been conducted in preclinical species and humans. Izencitinib is orally active, with good oral bioavailability. The compound's gut-restricted design results in low systemic exposure, with high concentrations in intestinal tissue and low concentrations in plasma. This pharmacokinetic profile is intended to minimize systemic side effects while providing local efficacy in the gastrointestinal tract.
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| Toxicity/Toxicokinetics |
In clinical trials, izencitinib has been generally well-tolerated. The gut-restricted design of the compound is intended to minimize the systemic side effects associated with JAK inhibitors, such as infections, hematologic abnormalities, and lipid elevations. Common adverse effects observed in clinical trials include gastrointestinal disturbances, which are consistent with the compound's local activity in the gut.
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| References |
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| Additional Infomation |
Izencitinib is being investigated in the clinical trial NCT03920254 (TD-1473 Long-Term Safety (LTS) Study of Ulcerative Colitis (UC)).
Drug Indication Treatment of Crohn's Disease Izencitinib (TD-1473, JNJ-8398) is an orally active, gut-restricted pan-JAK inhibitor being developed for the treatment of inflammatory bowel diseases, including ulcerative colitis and Crohn's disease. The compound has pKi values of 10.0, 10.0, 8.8, and 9.5 for JAK1, JAK2, JAK3, and TYK2, respectively. Izencitinib's gut-restricted design is intended to provide local efficacy in the gastrointestinal tract while minimizing systemic exposure and the associated side effects. The compound represents a novel approach to IBD therapy, offering the potential for potent JAK inhibition with a favorable safety profile. |
| Molecular Formula |
C22H26N8
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|---|---|
| Molecular Weight |
402.50
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| Exact Mass |
402.228
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| CAS # |
2051918-33-1
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| PubChem CID |
124090478
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| Appearance |
Yellow to orange solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
691.8±55.0 °C at 760 mmHg
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| Flash Point |
372.2±31.5 °C
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| Vapour Pressure |
0.0±2.2 mmHg at 25°C
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| Index of Refraction |
1.712
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| LogP |
3.22
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
30
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| Complexity |
620
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CC1=CC(=NN1)NC2=NC(=C3C=CC=NC3=C2)NC4C[C@H]5CC[C@@H](C4)N5CCC#N
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| InChi Key |
DADAEARVGOQWHV-ALOPSCKCSA-N
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| InChi Code |
InChI=1S/C22H26N8/c1-14-10-21(29-28-14)26-20-13-19-18(4-2-8-24-19)22(27-20)25-15-11-16-5-6-17(12-15)30(16)9-3-7-23/h2,4,8,10,13,15-17H,3,5-6,9,11-12H2,1H3,(H3,25,26,27,28,29)/t15?,16-,17+
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| Chemical Name |
3-[(1R,5S)-3-[[7-[(5-methyl-1H-pyrazol-3-yl)amino]-1,6-naphthyridin-5-yl]amino]-8-azabicyclo[3.2.1]octan-8-yl]propanenitrile
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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 : ~50 mg/mL (~124.22 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.21 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 (6.21 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 | 2.4845 mL | 12.4224 mL | 24.8447 mL | |
| 5 mM | 0.4969 mL | 2.4845 mL | 4.9689 mL | |
| 10 mM | 0.2484 mL | 1.2422 mL | 2.4845 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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