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Purity: ≥98%
DEL-22379 is a novel, potent, selective, and water-soluble dimerization inhibitor of ERK (extracellular signal-related kinase 2) with potential antitumor activity. Its IC50 for inhibiting ERK is 0.5 μM. Nearly 50% of all human cancers exhibit aberrant RAS-ERK signaling, making it a prime candidate for antineoplastic agent intervention. DEL-22379 prevents tumorigenesis caused by oncogenes of the RAS-ERK pathway by inhibiting ERK dimerization without affecting ERK phosphorylation. Even at low nanomolar concentrations, DEL-22379 can bind to ERK2 with a Kd that is estimated to be in the low micromolar range.
| Targets |
ERK2 (IC50 = 0.5 μM)
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|---|---|
| ln Vitro |
DEL-22379 is an ERK dimerization inhibitor.With an estimated half-maximal inhibitory concentration (IC50) of ~0.5 μM, DEL-22379 prevents EGF-induced co-immunoprecipitation of ectopic ERK2 molecules tagged with hemagglutinin (HA) or FLAG epitopes. Tumor cells that contain oncogenes from the RAS-ERK pathway experience growth inhibition. On tumor cells in culture, the biological effects of DEL-22379 are being studied. By comparing their half-maximal growth inhibitory concentrations (GI50), the cytostatic effects of DEL-22379 are contrasted to those of the MEK inhibitor PD-0325901 and the ERK kinase inhibitor SCH-772984. The three compounds are most toxic to cell lines containing mutant BRAF. In contrast, BRAF and RAS wild-type (WT) cell lines are the most resilient, and RAS mutant cells display a range of sensitivities. Because DEL-22379 exhibits similar dimerization- and cytoplasmic signaling-inhibitory dose responses (IC50 of 150-400 nM) regardless of genotype, distinct sensitivity to it cannot be explained in cells with different oncogenic genotypes[1].
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| ln Vivo |
Some of the aforementioned cell lines are xenografted onto nude mice to test the antitumor effects of DEL-22379. Tumor growth is then observed after intra-peritoneal injection of DEL-22379 at a dose of 15 mg/kg. Both liver extracts and xenografted tumors exhibit inhibition of ERK dimerization at this dose. For A375 cells (BRAF mutants), DEL-22379 significantly slows tumor progression[1].
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| Enzyme Assay |
Compound screening is carried out in HEK293T cells that have been pretreated for 30 min with the potential inhibitors (10 μM) before being stimulated with EGF. By using native PAGE and p-ERK evaluation of the potential positives, cellular lysates are examined for the presence of ERK dimerization. When His-ERK2 and DEL-22379 are added to purified GST-MEK1 ΔN EE that has been purified from bacteria and bound to glutathione sepharose beads, in vitro ERK dimerization is measured. Additionally carried out are Western blotting, kinase assays, and luciferase assays. The DEL-22379 compound is in silico docked using the modeling tools offered by the OpenEye package (v. 2.1).
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| Cell Assay |
DEL-22379 (0.2-1 μM) is applied to HEK293T cells that have been plated at a density of 1,000–2,000 cells per well for 48 hours. Alamar Blue is then added, and the colorimetric change is measured at 570 and 600 nm. Using GraphPad5 Prism Software, nonlinear regression is used to estimate the GI50. By measuring caspase 3 activity, either through western blotting or the Caspase-Glo 3/7 luminogenic assay, apoptosis is examined[1].
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| Animal Protocol |
Mice: In female, athymic nu/nu mice that are eight weeks old, cancer cells are xenografted. Prior to treatment with DEL-22379 at a dose of 15 mg/kg every 12 hours for two weeks, 3×106 cells are injected subcutaneously in the lateral flank and given time to mature for 10 to 15 days. Patient-derived xenografts (PDXs) are procedures utilizing patient-derived colorectal cancer cells carrying the BRAFV600E mutation from non-necrotic areas of primary adenocarcinomas from patients who undergo surgical resection. NOD-SCID mice have cell grafts placed in their cecum or both flanks. DEL-22379 is injected intraperitoneally at a concentration of 15 mg/kg every 12 hours for 30 days[1].
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| References | |
| Additional Infomation |
DEL-22379 is an oxindole that is 5-amino-oxindole in which the 5-amino group has undergone formal condensation with the carboxy group of 3-(piperidin-1-yl)propanoic acid to give the corresponding carboxamide and in which the hydrogens at position 3 have been replaced by a (5-methoxy-1H-indol-3-yl)methylene group (Z configuration). It is an inhibitor of extracellular signal-regulated kinase (ERK) dimerisation. It has a role as an ERK dimerisation inhibitor and an antineoplastic agent. It is a member of piperidines, a member of oxindoles, an enamide and a secondary carboxamide.
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| Molecular Formula |
C26H28N4O3
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|---|---|---|
| Molecular Weight |
444.53
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| Exact Mass |
444.216
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| Elemental Analysis |
C, 70.25; H, 6.35; N, 12.60; O, 10.80
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| CAS # |
181223-80-3
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| Related CAS # |
181223-80-3;DEL22379 HCl;
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| PubChem CID |
11224574
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| Appearance |
Yellow to orange solid
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
763.9±60.0 °C at 760 mmHg
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| Flash Point |
415.8±32.9 °C
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| Vapour Pressure |
0.0±2.6 mmHg at 25°C
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| Index of Refraction |
1.697
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| LogP |
3.13
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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 |
6
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| Heavy Atom Count |
33
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| Complexity |
750
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C([H])([H])C([H])([H])N1C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H])N([H])C1C([H])=C([H])C2=C(C=1[H])/C(/C(N2[H])=O)=C(/[H])\C1=C([H])N([H])C2C([H])=C([H])C(=C([H])C1=2)OC([H])([H])[H]
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| InChi Key |
INQUULPXCZAKMS-XKZIYDEJSA-N
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| InChi Code |
InChI=1S/C26H28N4O3/c1-33-19-6-8-23-20(15-19)17(16-27-23)13-22-21-14-18(5-7-24(21)29-26(22)32)28-25(31)9-12-30-10-3-2-4-11-30/h5-8,13-16,27H,2-4,9-12H2,1H3,(H,28,31)(H,29,32)/b22-13-
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| Chemical Name |
N-[(3Z)-3-[(5-methoxy-1H-indol-3-yl)methylidene]-2-oxo-1H-indol-5-yl]-3-piperidin-1-ylpropanamide
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.62 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2496 mL | 11.2478 mL | 22.4957 mL | |
| 5 mM | 0.4499 mL | 2.2496 mL | 4.4991 mL | |
| 10 mM | 0.2250 mL | 1.1248 mL | 2.2496 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.
Identification and Validation of DEL-22379 as an ERK Dimerization Inhibitor. Cancer Cell. 2015 Aug 10;28(2):170-82. |
Antitumor Effects of DEL-22379 in Mice. Cancer Cell. 2015 Aug 10;28(2):170-82. |
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