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IRAK inhibitor 1 is a potent IRAK-4 inhibitor with IC50 of 216 nM, is poorly active against JNK-1 and JNK-2 with IC50 of 3.801 μM, and >10 μM, respectively.
| Targets |
IRAK‑4 (Interleukin‑1 receptor‑associated kinase 4). IRAK inhibitor 1 are reported in the provided literature. The compound showed “significant potency” in an IRAK‑4 enzyme assay, and its methyl‑capped analogue (compound 4) retained similar levels of potency (reported IRAK‑4 IC₅₀ = 200 nM for compound 4). IRAK inhibitor 1 was poorly active against JNK‑1 and JNK‑2 . [1]
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| ln Vitro |
Although less effective against JNK-1 and JNK-2, IRAK inhibitor 1 exhibits considerable activity in the IRAK-4 enzyme assay [1]. A recent addition to the IRAK family, IRAK-4 has special functional characteristics. The closest human homologue to Pelle is IRAK-4. Overexpression of IRAK-4 can activate the NF-κB and mitogen-activated protein (MAP) kinase pathways. Endogenous IRAK-4 interacts with IRAK-1 and TRAF6 in an IL-1-dependent manner. Most remarkably, IRAK-4 depends on its kinase activity to activate NF-κB, unlike other IRAKs. Moreover, IRAK-4 has the ability to phosphorylate IRAK-1, and dominant-negative IRAK-4 overexpression prevents IL-1-induced IRAK-1 activation and modification, suggesting that IRAK-4 is a key component of Toll/IL Early signaling by the -1 receptor (upstream of IRAK-1). Like other IRAKs, IRAK-4 can activate the NF-κB and MAPK signal transduction pathways. It also shares the same domain structure. It is not functionally redundant with IRAK-1, but it associates quickly and momentarily in an IL-1-dependent way with TRAF6 and IRAK-1. To activate NF-κB, IRAK-4, an active protein kinase, must have kinase activity. Upstream of IRAK-1, IRAK-4 may act as an IRAK-1 activator [2].
IRAK inhibitor 1 was evaluated for its ability to inhibit IRAK‑4 in an enzyme assay, showing significant potency. Its methyl‑capped derivative (compound 4) exhibited similar IRAK‑4 inhibitory activity, suggesting that the bidentate hydrogen‑bond acceptor/donor (HBA/HBD) binding mode of the aminopyrimidine is not responsible for the activity. The O‑linked pyrimidine analogue (compound 5), which lacks the aminopyrimidine motif, still displayed low‑micromolar activity. Regioisomeric pyridines (compounds 6 and 7) showed contrasting SAR: the 2,6‑pyridine isomer (6) had low‑nanomolar potency, whereas the 2,4‑pyridine isomer (7) was weakly active despite possessing a more accessible bidentate binding motif. IRAK inhibitor 1 was also poorly active against JNK‑1 and JNK‑2, in contrast to its activity against IRAK‑4. [1] |
| Enzyme Assay |
The IRAK‑4 enzyme assay used to determine the potency of IRAK inhibitor 1 is not described in detail in the provided text. The compound was tested in an IRAK‑4 enzyme assay where it showed significant potency. Additionally, cross‑screening was performed against JNK‑1 and JNK‑2, where IRAK inhibitor 1 was poorly active. No specific assay protocols (e.g., ATP concentrations, incubation times, detection methods) are provided. [1]
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| References | |
| Additional Infomation |
IRAK inhibitor 1 originated from a JNK kinase programme and was discovered via routine cross‑screening of final compounds and advanced intermediates across kinase projects at UCB. Its binding mode was inferred using a combination of in silico docking into an IRAK‑4 homology model, surrogate crystal structure analysis (using JNK‑3 co‑crystal structures of related analogues), and chemical analogue SAR. Docking suggested that the imidazo[1,2‑a]pyridine nitrogen (N1) binds to the hinge backbone (Met265) of IRAK‑4, while the aminopyrimidine moiety acts primarily as a linking scaffold. The piperidine ring nitrogen was proposed to sit in the anionic pocket formed by Asp329 and the carbonyl backbones of Asn316 and Ala315. This binding mode was supported by the crystal structure of a closely related 2‑methylated aminopyrimidine analogue (compound 8) in JNK‑3, which is incapable of forming the typical bidentate interaction. The validity of the IRAK‑4 homology model was later corroborated by published crystallographic data from Amgen (formerly Tularik). The work demonstrates the value of cross‑fertilisation between medicinal chemistry projects for hit finding. [1]
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| Molecular Formula |
C17H19N5
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|---|---|
| Molecular Weight |
293.36626
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| Exact Mass |
293.164
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| CAS # |
1042224-63-4
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| PubChem CID |
44449078
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
2.962
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
22
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| Complexity |
357
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
HUYUPQNBDBTPQQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H19N5/c1-2-11-22-15(12-19-17(22)6-1)14-4-3-5-16(21-14)20-13-7-9-18-10-8-13/h1-6,11-13,18H,7-10H2,(H,20,21)
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| Chemical Name |
6-imidazo[1,2-a]pyridin-3-yl-N-piperidin-4-ylpyridin-2-amine
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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 : ~16.67 mg/mL (~56.82 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.67 mg/mL (5.69 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 16.7 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: ≥ 1.67 mg/mL (5.69 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 16.7 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: ≥ 1.67 mg/mL (5.69 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 | 3.4087 mL | 17.0433 mL | 34.0866 mL | |
| 5 mM | 0.6817 mL | 3.4087 mL | 6.8173 mL | |
| 10 mM | 0.3409 mL | 1.7043 mL | 3.4087 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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