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| Targets |
Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2 or MK-2) (IC50 = 0.0085 ± 0.0016 µM).
The compound also shows activity against closely related kinases MK-3 (IC50 = 0.21 µM) and PRAK (MK-5) (IC50 = 0.081 µM). It demonstrates high selectivity against many other kinases including CDK2 (IC50 > 200 µM), ERK2 (IC50 > 10 µM), JNK2 (IC50 > 200 µM), IKK2 (IC50 > 200 µM), p38α (IC50 > 10 µM), MNK1 (IC50 > 10 µM), MSK1 (IC50 > 200 µM), and MSK2 (IC50 > 200 µM). The inhibitors are competitive with ATP.[1] |
|---|---|
| ln Vitro |
MK2-IN-3 hydrate has an IC50 of 4.4 μM and can decrease TNFα production in U397 cells [1].
Compound 16 is one of the most potent inhibitors identified in the series against the isolated MK-2 enzyme, with an IC50 of 8.5 nM. However, in the U937 cellular assay measuring inhibition of LPS-stimulated TNFα production, its potency is significantly attenuated, with an IC50 of 4.4 µM. This discrepancy is attributed to factors such as competition with high intracellular ATP concentrations and potentially suboptimal physical properties (e.g., low aqueous solubility, reported as < 0.4 µM).[1] |
| Enzyme Assay |
Compound 16 was tested in a biochemical assay to determine its IC50 against the MK-2 enzyme. The detailed assay protocol is not fully described in the provided text, but it involved measuring kinase activity under conditions where ATP concentrations were set at the Km value for MK-2 (30 µM) to allow for accurate potency and selectivity comparisons. The compound was confirmed to be ATP-competitive. Selectivity profiling was performed against a panel of other kinases under similar standardized ATP concentration conditions.[1]
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| Cell Assay |
Compound 16 was tested in a cell-based assay using U937 monocytic cells. The cells were stimulated with lipopolysaccharide (LPS) to induce TNFα production. The compound was added to the culture, and the inhibition of TNFα release into the supernatant was quantified after a specified incubation period (likely 4 hours, based on context). The IC50 value of 4.4 µM reflects its potency in this cellular context.[1]
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| ADME/Pharmacokinetics |
Compound 16 has extremely low water solubility, reported to be below 0.4 µM. Despite its high enzyme activity (IC50 = 8.5 nM), its cellular activity is low (IC50 = 4.4 µM), which is considered to be one of the reasons for its reduced cellular activity. Other ADME parameters of compound 16 (e.g., permeability, plasma protein binding, clearance, oral bioavailability) are not provided in the literature. [1]
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| References | |
| Additional Infomation |
Compound 16 (a 3-quinoline derivative) is a structural analog in the pyrrolopyridone series and exhibits extremely high enzymatic activity against MK-2 (IC50 in the single-digit nanomolar range). It embodies a structure-activity relationship, where a large, rigid aromatic group (such as quinoline) at the 2-position of the pyridine ring significantly enhances the binding affinity to MK-2, likely due to its unique hydrophobic pocket in the kinase hinge region. However, this also highlights a key challenge for this series of compounds: how to translate high enzymatic activity into effective cellular activity. In this case, poor physicochemical properties (especially solubility) and competition with intracellular ATP hinder this conversion. [1]
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| Molecular Formula |
C21H18N4O2
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|---|---|
| Molecular Weight |
358.393224239349
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| Exact Mass |
358.142
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| CAS # |
1186648-22-5
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| Related CAS # |
MK2-IN-3;724711-21-1
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| PubChem CID |
25163932
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| Appearance |
Off-white to light yellow solid powder
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
27
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| Complexity |
526
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
NIKCVKMHGQQSRN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H16N4O.H2O/c26-21-16-11-20(25-18(16)6-8-23-21)14-5-7-22-19(10-14)15-9-13-3-1-2-4-17(13)24-12-15;/h1-5,7,9-12,25H,6,8H2,(H,23,26);1H2
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| Chemical Name |
2-(2-quinolin-3-ylpyridin-4-yl)-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one;hydrate
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7903 mL | 13.9513 mL | 27.9026 mL | |
| 5 mM | 0.5581 mL | 2.7903 mL | 5.5805 mL | |
| 10 mM | 0.2790 mL | 1.3951 mL | 2.7903 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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