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Purity: ≥98%
CC-90003 is a novel, potent, selective, orally bioavailable, and irreversible (covalent) inhibitor of ERK1/2 (extracellular signal-regulated kinase) with IC50s in the 10-20 nM range, and displays good kinase selectivity in a 258-kinase biochemical assay. In KRAS and BRAF mutant tumors, CC-90003 exhibits powerful anti-proliferative activity. ERK activity is inhibited by CC-90003, which also stops ERK-mediated signal transduction pathways from being activated. As a result, the proliferation and survival of ERK-dependent tumor cells are inhibited. The management of tumors driven by mutant RAS or BRAF may benefit from ERK inhibition; however, the proof-of-concept demonstration of CC-90003 was constrained by a dearth of objective responses, a poor PK profile, and unanticipated neurotoxicity.
| Targets |
ERK1; ERK2
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| ln Vitro |
CC-90003 was discovered to strongly inhibit the kinase activities of ERK1 and ERK2 with IC50s in the range of 10 to 20 nmol/L and had good kinase selectivity in biochemical, cellular, and mass spectrometry assays of 347 kinases. A 258-kinase biochemical assay panel revealed that CC-90003 significantly inhibited 213 kinases (50% inhibition), moderately inhibited 28 kinases (50%-80% inhibition), and significantly inhibited 17 kinases (>80% inhibition). A375 BRAF V600E-mutant melanoma cell line was used in an ActivX cellular kinase screening, and only 5 of 194 kinases (ERK1, ERK2, MKK4, MKK6, and FAK) were inhibited by >80% at 1 mmol/L of CC-90003. In a Cerep panel of 40 nonkinase enzymes and receptors, no significant inhibition (14%) was observed at the same concentration. Only 3 kinases, KDR, FLT3, and PDGFRa, were inhibited in cells at biologically significant concentrations through our iterative analyses, in addition to ERK1/2. CC-90003 was particularly effective against tumors with BRAF mutations. Many times, but not always, CC-90003 had cytotoxic effects on PDAC, lung cancer, and colorectal cancer cell lines that were KRAS-mutant. CC-90003 does not significantly reduce the proliferation of healthy bronchial epithelial cells or lung fibroblasts[1].
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| ln Vivo |
Although CC-90003 was well tolerated at a variety of doses (12.5 mg bi-daily to 100 mg thrice-daily) in in vivo studies using an HCT-116 xenograft model, doses of 50 mpk bi-daily and 75 mpk bi-daily caused mortality by study days 6 to 18. Inhibition of tumor growth occurs with both dosing regimens (qd and b.i.d.). CC-90003 inhibits the development of three PDX models with KRAS mutations in vivo[1].
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| Cell Assay |
The cells were plated on 96-well clear bottom black-well plates at a density of 3,000 cells per well in 90 mL of growth medium, and they were then incubated overnight at 37 C with 5% CO2 under standard cell culture growth conditions. The next day, one plate per cell line was used for the "Day 0" cell growth control readout, and the remaining plates received treatment with DMSO as a control and 9-point 3-fold dilutions of one compound or a combination of compounds. Three duplicates of each concentration were tested. At 72 hours, cell viability was assessed.
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| Animal Protocol |
Female athymic nude mice inoculated subcutaneously with 5×106 HCT-116 cancer cells
100 mg/kg qd and 50 mg/kg qd; 25 mg/kg b.i.d. and 12.5 mg/kg b.i.d. orally |
| References |
| Molecular Formula |
C22H21F3N6O2
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|---|---|---|
| Molecular Weight |
458.44
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| Exact Mass |
458.17
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| Elemental Analysis |
C, 57.64; H, 4.62; F, 12.43; N, 18.33; O, 6.98
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| CAS # |
1621999-82-3
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| Related CAS # |
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| PubChem CID |
90331177
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| Appearance |
White to off-white solid powder
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| LogP |
4.6
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
33
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| Complexity |
667
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
ILUKRINUNLAVMH-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H21F3N6O2/c1-5-18(32)28-17-8-12(2)6-7-15(17)29-20-14(22(23,24)25)11-27-21(31-20)30-16-9-19(33-4)26-10-13(16)3/h5-11H,1H2,2-4H3,(H,28,32)(H2,26,27,29,30,31)
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| Chemical Name |
N-[2-[[2-[(2-methoxy-5-methylpyridin-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]-5-methylphenyl]prop-2-enamide
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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 (5.45 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 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. Solubility in Formulation 2: 2.5 mg/mL (5.45 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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 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: ≥ 2.5 mg/mL (5.45 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 | 2.1813 mL | 10.9066 mL | 21.8131 mL | |
| 5 mM | 0.4363 mL | 2.1813 mL | 4.3626 mL | |
| 10 mM | 0.2181 mL | 1.0907 mL | 2.1813 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02313012 | Terminated | Drug: CC-90003 | Neoplasm Metastasis | Celgene | January 5, 2015 | Phase 1 |
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