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| Targets |
Londamocitinib (AZD4604; JAK1-IN-7) targets Janus kinase 1 (JAK1) (IC50 = 0.003 μM for human JAK1 kinase activity; Ki = 0.0015 μM) [2][3]
Londamocitinib (AZD4604; JAK1-IN-7) shows high selectivity over other JAK family members (JAK2: IC50 = 0.32 μM; JAK3: IC50 = 0.45 μM; TYK2: IC50 = 0.28 μM; selectivity indices > 90 vs. JAK1) [2][3] Londamocitinib (AZD4604; JAK1-IN-7) exhibits no significant inhibition of 450+ other kinases (IC50 > 10 μM) [2] |
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| ln Vitro |
- JAK1 kinase inhibitory activity: Londamocitinib (AZD4604; JAK1-IN-7) potently inhibits recombinant human JAK1 kinase activity in a dose-dependent manner, with IC50 = 0.003 μM and Ki = 0.0015 μM. It competitively binds to the ATP-binding pocket of JAK1 [2][3]
- Inhibition of JAK1-mediated signaling: The compound (0.001-0.1 μM) dose-dependently blocks IL-4/IL-13-induced STAT6 phosphorylation and IL-6-induced STAT3 phosphorylation in human peripheral blood mononuclear cells (PBMCs) and bronchial epithelial cells (BECs). At 0.01 μM, STAT6 phosphorylation is reduced by 85% (IL-4-induced) and 82% (IL-13-induced) [2][3] - Suppression of pro-inflammatory mediator production: Londamocitinib (AZD4604; JAK1-IN-7) (0.005-0.1 μM) inhibits IL-4/IL-13-induced eotaxin-1, MUC5AC, and IL-5 production in BECs and lung fibroblasts. At 0.05 μM, eotaxin-1 and MUC5AC levels are reduced by 70% and 65% respectively [2][3] - High kinase selectivity: The compound shows minimal inhibition of JAK2, JAK3, and TYK2 (IC50 > 0.28 μM) and no significant activity against 450+ other kinases (e.g., EGFR, ERK, CDK2) at 10 μM [2] - Minimal cytotoxicity: At concentrations up to 20 μM, Londamocitinib (AZD4604; JAK1-IN-7) exhibits no obvious cytotoxicity to BECs, PBMCs, or normal human lung fibroblasts (cell viability > 90%) [2][3] |
| ln Vivo |
- Efficacy in OVA-induced allergic asthma mouse model: BALB/c mice with OVA-induced asthma were administered Londamocitinib (AZD4604; JAK1-IN-7) via inhalation (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg) once daily for 7 days. The 1 mg/kg dose reduces airway eosinophilic infiltration by 80%, peribronchial inflammation by 75%, and BAL fluid IL-4/IL-5/IL-13 levels by 70-78% compared to vehicle control. It also improves airway hyperresponsiveness (AHR) to methacholine (PC20 increased by 2.3-fold) [2][3]
- Lung-targeted distribution: Inhaled Londamocitinib (AZD4604; JAK1-IN-7) (1 mg/kg) achieves lung tissue concentration of 12 μM at 1 hour post-dose, with minimal systemic exposure (plasma concentration = 0.08 μM), resulting in a lung/plasma ratio of 150 [2] - Mechanism validation in vivo: Lung tissues from treated mice (1 mg/kg) show reduced JAK1 phosphorylation (72% reduction) and STAT6 phosphorylation (68% reduction) compared to control, confirming JAK1 pathway inhibition [2][3] - Tolerability: No significant body weight loss (< 5%) or obvious toxic signs (lethargy, respiratory distress) are observed in treated mice. Serum ALT, AST, creatinine, and urea nitrogen levels remain within normal ranges [2][3] |
| Enzyme Assay |
- JAK1 kinase activity assay: Recombinant human JAK1 catalytic domain was mixed with ATP (10 μM), peptide substrate (derived from STAT3), and gradient concentrations of Londamocitinib (AZD4604; JAK1-IN-7) (0.0001-1 μM) in kinase buffer (pH 7.5). The mixture was incubated at 30°C for 1 hour, and phosphorylated substrate was detected by HTRF assay. IC50 was calculated by plotting inhibition rate against drug concentration [2][3]
- Surface plasmon resonance (SPR) binding assay: Recombinant human JAK1 catalytic domain was immobilized on a sensor chip. Londamocitinib (AZD4604; JAK1-IN-7) at gradient concentrations (0.001-10 μM) was injected, and binding affinity was measured at 25°C. The equilibrium dissociation constant (KD) was 0.0012 μM, confirming high-affinity binding to JAK1 [2] - Kinase selectivity panel assay: Londamocitinib (AZD4604; JAK1-IN-7) (10 μM) was screened against a panel of 456 human kinases. Inhibition of each kinase was measured by radiometric assay or fluorescence-based assay to evaluate off-target activity [2] |
| Cell Assay |
- Cytokine-induced STAT phosphorylation assay: Human BECs or PBMCs were seeded into 6-well plates (5×10⁵ cells/well) and treated with Londamocitinib (AZD4604; JAK1-IN-7) (0.001-0.1 μM) for 1 hour, then stimulated with IL-4 (10 ng/mL) or IL-13 (10 ng/mL) for 30 minutes. Cells were lysed, and p-STAT6, total STAT6, p-JAK1, and GAPDH were detected by western blot. Band intensities were quantified by densitometry [2][3]
- Pro-inflammatory mediator production assay: Human lung fibroblasts were seeded into 96-well plates (1×10⁴ cells/well) and pre-treated with Londamocitinib (AZD4604; JAK1-IN-7) (0.005-0.1 μM) for 1 hour, then stimulated with IL-4/IL-13 (10 ng/mL each) for 24 hours. Culture supernatants were collected, and eotaxin-1, MUC5AC, and IL-5 levels were measured by ELISA [2][3] - Cell viability assay: BECs, PBMCs, and normal human lung fibroblasts were seeded into 96-well plates (5×10³ cells/well) and treated with Londamocitinib (AZD4604; JAK1-IN-7) (0.001-20 μM) for 72 hours. Cell viability was measured by tetrazolium salt-based assay [2][3] |
| Animal Protocol |
- OVA-induced allergic asthma mouse model: 6-week-old BALB/c mice were sensitized with OVA/alum intraperitoneally on days 0 and 14, then challenged with OVA aerosol (1% w/v) on days 21-27 to induce asthma. Mice were randomly divided into vehicle control and Londamocitinib (AZD4604; JAK1-IN-7) inhalation groups (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, n=8 per group). The compound was formulated as an aqueous suspension and administered via nebulization once daily for 7 days (days 21-27). On day 28, mice were subjected to AHR measurement, then sacrificed for BAL fluid analysis and lung tissue histopathology [2][3]
- Pharmacokinetic animal study: Sprague-Dawley rats and BALB/c mice were administered Londamocitinib (AZD4604; JAK1-IN-7) via inhalation (1 mg/kg) or intravenous injection (0.1 mg/kg). Blood, lung, liver, kidney, and brain samples were collected at 0.25, 0.5, 1, 4, 8, and 24 hours post-dose. Drug concentrations were measured by LC-MS/MS to determine tissue distribution and pharmacokinetic parameters [2] |
| ADME/Pharmacokinetics |
Absorption: Inhaled Londamocitinib (AZD4604; JAK1-IN-7) was rapidly absorbed in the lungs, with a Tmax of 0.5 hours in mouse lung tissue. The pulmonary bioavailability after inhalation was 85%[2] - Distribution: The compound has high lung targeting, with a lung/plasma concentration ratio of 150 in mice and 120 in rats 1 hour after inhalation. It was poorly distributed in other tissues (liver:lung/liver ratio = 25; kidney:lung/kidney ratio = 30; brain: not detected)[2] - Metabolism: Londamocitinib (AZD4604; JAK1-IN-7) showed good metabolic stability in human and mouse liver microsomes, with half-lives (t1/2) of 9.5 hours (human) and 8.2 hours (mouse), respectively. It is mainly metabolized by oxidative demethylation and has no major toxic metabolites [2][3]
- Excretion: In mice, the half-life (t1/2) of elimination from lung tissue is 6.8 hours. Approximately 70% of the inhaled dose is excreted in feces and 20% in urine (mainly in unchanged form) [2] - Plasma protein binding: In human plasma, the plasma protein binding rate is 95.3 ± 1.2% (equilibrium dialysis method) [2][3] |
| Toxicity/Toxicokinetics |
Acute toxicity: No deaths or obvious toxic symptoms (weight loss, respiratory distress) were observed in mice and rats after a single inhalation dose of up to 10 mg/kg of Londamocitinib (AZD4604; JAK1-IN-7), with a maximum tolerated dose (MTD) > 10 mg/kg [2][3] - Subacute toxicity: No significant changes in body weight, blood parameters (white blood cells, red blood cells, platelets) or liver and kidney function indicators (ALT, AST, creatinine, blood urea nitrogen) were observed in mice treated with Londamocitinib (AZD4604; JAK1-IN-7) (1 mg/kg, inhalation, once daily for 28 days). Histopathological examination of the lungs, heart, liver, spleen and kidneys revealed no abnormal lesions (e.g., inflammation, fibrosis) [2][3]
- Pulmonary safety: No pulmonary irritation, edema or epithelial damage was observed in mice at inhaled doses up to 1 mg/kg. The total cell count and inflammatory cytokine levels (TNF-α, IL-6) in bronchoalveolar lavage fluid remained unchanged compared with the control group [2][3] - Drug interactions: No significant inhibition or induction of CYP450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) was observed at therapeutic concentrations [2] |
| References | |
| Additional Infomation |
Chemical Classification: Londamocitinib (AZD4604; JAK1-IN-7) is a small-molecule selective JAK1 inhibitor belonging to the pyrazolopyrimidine derivative class [2][3] - Mechanism of Action: This compound binds to the ATP-binding pocket of JAK1 and selectively inhibits its kinase activity. This blocks the phosphorylation of downstream STAT proteins (STAT3, STAT6) of JAK1-mediated pro-inflammatory cytokines (IL-4, IL-5, IL-13), thereby inhibiting allergic inflammation and airway hyperresponsiveness in asthma [2][3] - Target Background: JAK1 is a non-receptor tyrosine kinase that mediates the signaling of Th2 cytokines (IL-4, IL-5, IL-13), which play a key role in the pathogenesis of asthma. Aberrant JAK1 activation can lead to excessive airway inflammation, eosinophilic infiltration, and excessive mucus secretion[2][3]
- Therapeutic potential: Londamocitinib (AZD4604; JAK1-IN-7) is a potent, selective inhaled JAK1 inhibitor that targets the lungs for delivery with very low systemic exposure. It has shown good efficacy in preclinical asthma models and has potential value in the treatment of allergic asthma[2][3] - Route of administration: Inhaled formulations (nebulized suspensions) are designed to act locally on the lungs, thereby reducing the systemic side effects associated with oral JAK inhibitors[2][3] |
| Molecular Formula |
C28H31F2N7O4S
|
|---|---|
| Molecular Weight |
599.652051210403
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| Exact Mass |
599.212
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| CAS # |
2241039-81-4
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| PubChem CID |
135240395
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| Appearance |
White to off-white solid powder
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| LogP |
2.2
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| Hydrogen Bond Donor Count |
3
|
| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
9
|
| Heavy Atom Count |
42
|
| Complexity |
1010
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
S(C)(C1C=CC=C(C=1F)NC1=NC=C(C(C2=CNC3C2=CC=CC=3NC([C@@H](COC)N2CCN(C)CC2)=O)=N1)F)(=O)=O
|
| InChi Key |
JNUZADQZHYFJGW-JOCHJYFZSA-N
|
| InChi Code |
InChI=1S/C28H31F2N7O4S/c1-36-10-12-37(13-11-36)22(16-41-2)27(38)33-21-8-4-6-17-18(14-31-26(17)21)25-19(29)15-32-28(35-25)34-20-7-5-9-23(24(20)30)42(3,39)40/h4-9,14-15,22,31H,10-13,16H2,1-3H3,(H,33,38)(H,32,34,35)/t22-/m1/s1
|
| Chemical Name |
(2R)-N-[3-[5-fluoro-2-(2-fluoro-3-methylsulfonylanilino)pyrimidin-4-yl]-1H-indol-7-yl]-3-methoxy-2-(4-methylpiperazin-1-yl)propanamide
|
| 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 : ~71.43 mg/mL (~119.12 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.17 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 (4.17 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 | 1.6676 mL | 8.3382 mL | 16.6764 mL | |
| 5 mM | 0.3335 mL | 1.6676 mL | 3.3353 mL | |
| 10 mM | 0.1668 mL | 0.8338 mL | 1.6676 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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