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Purity: ≥98%
ERK5-IN-2 is a novel, potent, orally bioavailable, sub-micromolar, and selective ERK5 inhibitor with selectivity over p38α and BRD4. For ERK5 and ERK5 MEF2D, it has IC50 values of 0.82 μM, 3 μM, respectively. Both the growth of tumor xenografts and the angiogenesis induced by basic fibroblast growth factor (bFGF) in Matrigel plugs are inhibited by ERK5-IN-2. Endothelial cell angiogenesis and tumor cell motility are two cellular phenotypes that have been linked to extracellular regulated kinase 5 (ERK5) signaling. A series of pyrrole-2-carboxamides substituted at the 4-position with an aroyl group were found to exhibit IC50 values in the micromolar range, but had no selectivity against p38 MAP kinase. These novel ERK5 inhibitors, such as ERK5-IN-2, were discovered using high throughput screening. Truncation of the N-substituent attenuated the inhibition of p38α, which was important because it only slightly increased potency (∼3-fold) against ERK5. The selective inhibitor 4-(2-bromo-6-fluorobenzoyl)-N-(pyridin-3-yl)-1H-pyrrole-2-carboxamide (IC50 0.82 μM for ERK5; IC50 > 120 μM for p38α). This compound's complex crystal structure with ERK5 has been determined (PDB 5O7I). This substance was orally bioavailable and prevented tumor xenograft growth and bFGF-driven angiogenesis in Matrigel plugs. The selective ERK5 inhibitor that is described in this article offers a lead for further development into a tool compound for more in-depth studies looking to understand how ERK5 signaling affects cancer and other diseases.
| Targets |
ERK5 (IC50 = 0.82 μM); ERK5 MEF2D (IC50 = 3 μM)
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| ln Vivo |
ERK5-IN-2 (Compound 46) (cartilage; 100 mg/kg; 7 days in CD1 mice and 10 days in CD1 nude (nu/nu) mice) possesses low hemoglobin concentrations and anti-angiogenic properties [1]. In caco-2 cell permeability tests in humans and animals, ERK5-IN-2 (iv or intravenous 10 mg/kg for 0.083-24 hours) shows low internal clearance, high flux, and low efflux ratio (ER)
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| Animal Protocol |
Animal/Disease Models: Matrigel-vaccinated female CD1 mice (8-10 weeks old) and female CD1 nude (nu/nu) mice (8-10 weeks old) bearing A2780 human ovarian cancer xenografts [1]
Doses: 100 mg/1]. kg Route of Administration: Po; twice (two times) daily; 7 days for CD1 mice, 10 days for CD1 nude mice (nu/nu) Experimental Results: Significant reduction in tumor volume. Animal/Disease Models: 8-10 weeks old female CD1 mice [1] Doses: 10 mg/kg Route of Administration: intravenous (iv) (iv)injection or oral administration; 0.083-24 hrs (hrs (hours)) Experimental Results: The terminal plasma half-life is 38 minutes, and the plasma clearance rate is 27mL/ min/kg, oral bioavailability is 68%. |
| References |
[1]. Myers SM, et al. Identification of a novel orally bioavailable ERK5 inhibitor with selectivity over p38α and BRD4. Eur J Med Chem. 2019 May 25;178:530-543.
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| Molecular Formula |
C17H11BRFN3O2
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|---|---|
| Molecular Weight |
388.190546274185
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| Exact Mass |
387.00187
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| CAS # |
1888305-96-1
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| Related CAS # |
1888305-96-1
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| Appearance |
Solid
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| SMILES |
C1=CC(=C(C(=C1)Br)C(=O)C2=CNC(=C2)C(=O)NC3=CN=CC=C3)F
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| InChi Key |
ATKCERYALDNMPL-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H11BrFN3O2/c18-12-4-1-5-13(19)15(12)16(23)10-7-14(21-8-10)17(24)22-11-3-2-6-20-9-11/h1-9,21H,(H,22,24)
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| Chemical Name |
4-(2-bromo-6-fluorobenzoyl)-N-pyridin-3-yl-1H-pyrrole-2-carboxamide
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| Synonyms |
ERK5-IN 2; ERK5 IN-2; ERK5-IN-2
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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: 78~250 mg/mL (200.9~644.0 mM)
Ethanol: ~3 mg/mL (~7.7 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.36 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 20.8 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: ≥ 2.08 mg/mL (5.36 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 20.8 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: ≥ 2.08 mg/mL (5.36 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 | 2.5761 mL | 12.8803 mL | 25.7606 mL | |
| 5 mM | 0.5152 mL | 2.5761 mL | 5.1521 mL | |
| 10 mM | 0.2576 mL | 1.2880 mL | 2.5761 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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