CC-90003

Catalog No.S8801 Batch:S880101

Technical Data

Formula	C₂₂H₂₁F₃N₆O₂
Molecular Weight	458.44	CAS No.	1621999-82-3
Solubility (25°C)*	In vitro	DMSO	92 mg/mL (200.68 mM)
		Water	Insoluble
		Ethanol	Insoluble
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. * Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description

CC-90003 is an irreversible inhibitor of ERK1/2 with IC50s in the 10-20 nM range and shows good kinase selectivity in a 258-kinase biochemical assay.

Targets

ERK1 ^[1]

ERK2 ^[1]

In vitro

In biochemical, cellular, and mass spectrometry assays of 347 kinases, CC-90003 was found to strongly inhibit kinase activities of ERK1 and ERK2 with IC50s in the 10 to 20 nmol/L range and had good kinase selectivity. In a 258-kinase biochemical assay panel, significant inhibition of 213 kinases (<50% inhibition), moderate inhibition of 28 kinases (50%–80% inhibition), and >80% inhibition of 17 kinases by CC-90003 were found. In an ActivX cellular kinase screening using A375 BRAF V600E-mutant melanoma cell line, only 5 of 194 kinases (ERK1, ERK2, MKK4, MKK6, and FAK) were inhibited by >80% at 1 mmol/L of CC-90003. At the same concentration, no significant inhibition (<14%) was found in a Cerep panel of 40 nonkinase enzymes and receptors. Through our iterative analyses, only 3 kinases, in addition to ERK1/2, were inhibited in cells at biologically relevant concentrations: KDR, FLT3, and PDGFRa. Tumors with BRAF mutations were particularly sensitive to CC-90003. In many, but not all cases, CC-90003 had cytotoxic effects in KRAS-mutant PDAC, lung cancer, and colorectal cancer cell lines. CC-90003 does not significantly inhibit proliferation of normal lung fibroblasts or bronchial epithelial cells^[1].

In vivo

In in vivo studies of an HCT-116 xenograft model, CC-90003 was well tolerated at a range of doses (12.5 mg b.i.d.-100 mg qd), although doses of 50 mpk b.i.d. and 75 mpk b.i.d. group caused mortality by days 6 to 18 of study. Both dosing schedules (qd and b.i.d.) leads to tumor growth inhibition. CC-90003 inhibits tumor growth in vivo of three KRAS-mutant PDX models^[1].

Protocol (from reference)

Cell Assay:^{^[1]}	Cell lines KRAS-mutant cell lines Concentrations -- Incubation Time 72 h Method The cells were plated at a density of 3,000 cells/well in 90 mL of growth media on 96-well clear bottom black-well plates and incubated with overnight under standard cell culture growth conditions at 37 C with 5% CO2. The followinging day, one plate for each cell line was used for "Day 0" cell growth control readout, whereas others were treated with 9-point3-fold dilutions of one compound or combination of compounds, and a DMSO control. Each concentration was tested in triplicate. Cell viability was measured 72 hours later.
Animal Study:^{^[1]}	Animal Models Female athymic nude mice inoculated subcutaneously with 5×10⁶ HCT-116 cancer cells Dosages 100 mg/kg qd and 50 mg/kg qd; 25 mg/kg b.i.d. and 12.5 mg/kg b.i.d. Administration orally

Cell Assay:^{^[1]}

Cell lines
KRAS-mutant cell lines
Concentrations
--
Incubation Time
72 h
Method
The cells were plated at a density of 3,000 cells/well in 90 mL of growth media on 96-well clear bottom black-well plates and incubated with overnight under standard cell culture growth conditions at 37 C with 5% CO2. The followinging day, one plate for each cell line was used for "Day 0" cell growth control readout, whereas others were treated with 9-point3-fold dilutions of one compound or combination of compounds, and a DMSO control. Each concentration was tested in triplicate. Cell viability was measured 72 hours later.

Animal Study:^{^[1]}

Animal Models
Female athymic nude mice inoculated subcutaneously with 5×10⁶ HCT-116 cancer cells
Dosages
100 mg/kg qd and 50 mg/kg qd; 25 mg/kg b.i.d. and 12.5 mg/kg b.i.d.
Administration
orally

References

[1] Aronchik I, et al. Mol Cancer Res. 2018, doi: 10.1158/1541-7786.MCR-17-0554.

Selleck's CC-90003 has been cited by 1 publication

Targeting ERK induced cell death and p53/ROS-dependent protective autophagy in colorectal cancer [ Cell Death Discov, 2021, 7(1):375]	PubMed: 34864826

Targeting ERK induced cell death and p53/ROS-dependent protective autophagy in colorectal cancer [ Cell Death Discov, 2021, 7(1):375]

PubMed: 34864826

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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