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| Targets |
IRAK4-IN-28 targets interleukin-1 receptor-associated kinase 4 (IRAK4). It inhibits IRAK4 with an IC50 of 0.005 µM (5 nM). The compound also inhibits IRAK1 with an IC50 of 0.023 µM. It shows selectivity for IRAK4 over IRAK1, CDC-like kinase 1 (Clk1), and Clk3. By inhibiting IRAK4, it blocks downstream signaling pathways involved in inflammation.
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| ln Vitro |
AZ1495 (compound 28) (10 μM, 1 h) is kinase selective for IRAK4 with IC50 values of 0.005 μM (enzyme assay) and 0.052 μM (cell assay) [1]. AZ1495 (10 μM, 1 h) exhibits a kinase inhibitory effect on IRAK4, with an IC50 value of 0.005 μM and a Kd value of 0.0007 μM[1]. AZ1495 (0.001-100 μM, 72 h) suppresses NF-κB activation and proliferation of ABC-DLBCL cell line in a dose-dependent manner [1]. AZ1495 (0-3.3 μM, 14 hours) coupled with BTK inhibitors in OCI-LY10 cells totally suppresses NF-κB activation and promotes cell death at lower dosages [1].
IRAK4-IN-28 demonstrates potent in vitro activity as an IRAK4 inhibitor, with an IC50 of 0.005 µM (5 nM). It also inhibits IRAK1 with an IC50 of 0.023 µM. The compound shows good physicochemical and kinase selectivity for IRAK4 and IRAK1. These properties make it a valuable tool for studying the IRAK4-mediated signaling pathways in vitro. |
| ln Vivo |
AZ1495 (Compound 28) (orally, daily, 12.5 mg/kg) coupled with ibrutinib induced tumor regression in an ABC-DLBCL animal model (OCI-LY10 cells) [1]. AZ1495 (IV, 2 mg/kg and PO, 5 mg/kg) is characterized by high clearance (Cl) in rats (75 mL/min/kg) and moderate prediction based on hepatocyte data (Clint 15 μl /min/106 cells), anticipated clearance rate 42 mL/min/kg), poor bioavailability, consistent with significant first-pass impact [1]. Active renal secretion of AZ1495 (iv, 1 mg/kg) in dogs is low [1].
IRAK4-IN-28 is an orally bioactive inhibitor, indicating that it is suitable for in vivo administration. Its potent in vitro activity (IC50 = 5 nM for IRAK4) and good selectivity profile suggest that it would be effective in animal models of inflammatory diseases. The compound is expected to inhibit IRAK4-mediated signaling pathways in vivo, reducing the production of pro-inflammatory cytokines. |
| Enzyme Assay |
The primary in vitro assay for IRAK4-IN-28 is a kinase activity assay using purified recombinant IRAK4 enzyme. The assay measures the compound's ability to inhibit the phosphorylation of a substrate, and the IC50 is determined from dose-response curves. This cell-free system allows for the direct assessment of the compound's inhibitory potency against IRAK4 and its selectivity over other kinases.
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| Cell Assay |
Cell Viability Assay[1]
Cell Types: OCI-LY10 and SUDHL2 Cell Tested Concentrations: 0.001-100 μM Incubation Duration: 72 hrs (hours) Experimental Results: Inhibited the growth of OCI-LY10 cells in a dose-dependent manner, while GCB cell line SUDHL2 did not IRAK4 inhibitors are sensitive and do not increase cell killing. Cell death of OCI-LY10 cells increased upon increasing the concentrations of compound 28 and BTK ibrutinib. Western Blot Analysis[1] Cell Types: OCI-LY10 Cell Tested Concentrations: 0-3.3 μM Incubation Duration: 14 h Experimental Results: Inhibited IκBα phosphorylation in a dose-dependent manner in OCI-LY10 cells. Shown that combination with 10 nM ibrutinib induces apoptosis by cleaving caspase 3 in OCI-LY10 cells. In vitro cellular assays for IRAK4-IN-28 involve treating cells with the compound and measuring its effect on IRAK4-mediated signaling pathways. This can include measuring the phosphorylation of downstream targets or the production of pro-inflammatory cytokines. The compound's potency in cellular assays would confirm its ability to inhibit IRAK4 activity in a physiological context. |
| Animal Protocol |
Animal/Disease Models: CB.17 SCID (severe combined immunodeficient) mouse [1]
Doses: 12.5 mg/kg Route of Administration: po (po (oral gavage)) daily, 12.5 mg/kg Experimental Results: Single agents have modest antitumor activity, but ibrutinib combination can cause Tumor regression occurred and was well tolerated. Animal/Disease Models: Rat[1] Doses: 2 mg/kg, 5mg/kg Route of Administration: intravenous (iv) (iv)injection, 2 mg/kg and po (po (oral gavage)) 5mg/kg Experimental Results: Species dose (mg/kg) Cl (mL/min/ kg) Vss (L/kg) PO Half-life (h) IV Half-life (h) Fabs (%) F (%) Rat 2,5 75 2.1 2.0 0.8 100 28 Dog 1 29 3.0 - 3.3 - - Animal/Disease Models: dog [1 ] Doses: 1 mg/kg Route of Administration: iv., 1 mg/kg Experimental Results: Type dose (mg/kg) Cl (mL/min/kg) Vss (L/kg) PO half-life (h) IV half-life (h) Fab (%) F (%) Rat 2,5 75 2.1 2.0 0.8 100 28 Dog 1 29 3.0 - 3.3 - - In vivo animal experiments for IRAK4-IN-28 would involve oral administration of the compound to animal models of inflammatory diseases. The compound's efficacy would be assessed by measuring its effects on disease severity, inflammatory markers, and cytokine levels. Its oral bioavailability and pharmacokinetic properties would be characterized in these studies. |
| ADME/Pharmacokinetics |
IRAK4-IN-28 has a molecular weight of 385.5 and a molecular formula of C21H31N5O2. It is a weak base and is orally bioavailable. The compound is soluble in chloroform and DMSO. Its pharmacokinetic properties, such as half-life and tissue distribution, are not specified in the provided sources but are likely characterized for its use as an orally active research compound.
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| Toxicity/Toxicokinetics |
Toxicological data for IRAK4-IN-28 is not detailed in the provided sources. As a research compound, it is not intended for human use. Standard safety precautions should be followed when handling. Its safety profile would need to be established through preclinical studies if it were to be developed for therapeutic applications.
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| References | |
| Additional Infomation |
IRAK4-IN-28 (AZ1495) is a potent and orally bioactive inhibitor of IRAK4 with an IC50 of 5 nM. It also inhibits IRAK1 with an IC50 of 23 nM. The compound shows good physicochemical and kinase selectivity, making it a valuable tool for studying IRAK4-mediated inflammatory and immune signaling pathways. It is a weak base and is orally bioavailable, suitable for in vivo research applications.
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| Molecular Formula |
C21H31N5O2
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| Molecular Weight |
385.50314450264
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| Exact Mass |
385.247
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| CAS # |
2196204-23-4
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| PubChem CID |
131839619
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| Appearance |
White to off-white solid powder
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| LogP |
2.4
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
28
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| Complexity |
489
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O1CCN(CC1)C1CCC(CC1)NC1=C2C(=NC=N1)NC=C2C1CCOCC1
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| InChi Key |
DJVYXMINSBMUHH-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H31N5O2/c1-3-17(26-7-11-28-12-8-26)4-2-16(1)25-21-19-18(15-5-9-27-10-6-15)13-22-20(19)23-14-24-21/h13-17H,1-12H2,(H2,22,23,24,25)
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| Chemical Name |
N-(4-morpholin-4-ylcyclohexyl)-5-(oxan-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
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| Synonyms |
IRAK4IN28; IRAK4-IN-28; IRAK4 inhibitor 28
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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 : ~10 mg/mL (~25.94 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1 mg/mL (2.59 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 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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: ≥ 1 mg/mL (2.59 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 10.0 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. View More
Solubility in Formulation 3: ≥ 1 mg/mL (2.59 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5940 mL | 12.9702 mL | 25.9403 mL | |
| 5 mM | 0.5188 mL | 2.5940 mL | 5.1881 mL | |
| 10 mM | 0.2594 mL | 1.2970 mL | 2.5940 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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