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GDC-0623

GDC-0623

Catalog No.

B1135

MEK1 inhibitor, potent and ATP-uncompetitive

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Grouped product items
Size	Price	Stock
10mM (in 1mL DMSO)	$143.00	In stock
5mg	$136.00	In stock
25mg	$383.00	In stock
100mg	$768.00	In stock

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Background
Product Citation
Chemical Properties
Protocol
Biological Activity
Quality Control

Background

GDC-0623 is a potent and ATP-uncompetitive inhibitor of MEK1 with Ki value of 0.13nM [1].

GDC-0623 is an allosteric MEK inhibitor and has efficacy against both mutant BRAF and mutant KRAS. In the cell viability assays, GDC-0623 inhibits BRAF (V600E) and KRAS (G13D) with EC50 values of 7nM and 42nM, respectively in A375 cells and HCT116 cells. Besides that, GDC-0623 shows similar efficacy in the two genotypes in a panel of BRAF and KRAS-mutant cancer cell lines. GDC-0623 is found to prevent MEK phosphorylation in cells, resulting in more effective inhibition of pERK. Furthermore, it is found that GDC-0623 blocks RAF activation through the effect on MEK. It induces dimerization of MEK with both BRAF and CRAF and stabilizes the RAF–MEK complex. In addition, GDC-0623 also suppresses RAF activation via inhibiting the formation of BRAF–CRAF heterodimer and the translocation of RAF in plasma membrane [1].

References:
[1] Hatzivassiliou G, Haling J R, Chen H, et al. Mechanism of MEK inhibition determines efficacy in mutant KRAS-versus BRAF-driven cancers. Nature, 2013, 501(7466): 232-236.

Product Citation

1. White SM, Avantaggiati ML, et al. "YAP/TAZ Inhibition Induces Metabolic and Signaling Rewiring Resulting in Targetable Vulnerabilities in NF2-Deficient Tumor Cells." Dev Cell. 2019 May 6;49(3):425-443.e9. PMID:31063758

Chemical Properties

Physical Appearance	A solid
Storage	Store at -20°C
M.Wt	456.21
Cas No.	1168091-68-6
Formula	C₁₆H₁₄FIN₄O₃
Solubility	insoluble in H2O; ≥16.85 mg/mL in DMSO; ≥2.69 mg/mL in EtOH with ultrasonic
Chemical Name	5-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide
SDF	Download SDF
Canonical SMILES	C1=CC(=C(C=C1I)F)NC2=C(C=CC3=CN=CN32)C(=O)NOCCO
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Kinase experiment [1]:
In vitro Kinase assays	0.14 μM of purified inactive recombinant MEK-1 protein is preincubated with inhibitors in 15 μL of kinase buffer including (20 mM MOPS pH7.2, 25 mM beta glycerol phosphate, 5 mM EGTA, 1 mM sodium orthovanadate, 1 mM DTT, 100 μM ATP, 15 mM MgCl2). After incubating 10 minutes at 30°C, 1 ng of BRAF, CRAF or BRAF V600E combined with 0.5 μg of inactive recombinant ERK2 is added to the reaction in total volume of 20 μL. After incubating 30 minutes at 30°C the reaction is stopped by adding Laemmle sample buffer. Enzyme activity is measured by determining level of phosphor-MEK by SDS-PAGE. Immunoreactive proteins are visualized with SuperSignal West Pico Chemiluminescent Substrate.
Cell experiment [1, 2]:
Cell lines	KRAS mutant HCT116 or SW620 cells
Preparation method	Soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
Reacting condition	0.01-0.15 μmol/L; 3h-48 h;
Applications	GDC-0623 dose- and time-dependently up-regulated the pro-apoptotic BH3-only protein BIM in HCT116 cells or KRAS mutant HCT116 or SW620 cells. GDC-0623 inhibited cellular proliferation with EC50 values of 4 nM, 53 nM, 11 nM, 18 nM and 94 nM for A375 (BRAFV600E), HCT116 (KRASG13D), COLO 205, HT-29, and HCT116 cells, respectively.
Animal experiment [1]:
Animal models	Mice bearing A375, MiaPaCa-2, and HCT116 xenografts
Dosage form	40 mg/kg, oral gavage (PO), by mouth once a day, for 20 days
Applications	GDC-0623 showed tumour growth inhibition of 120% and 115% in MiaPaCa-2 and HCT116 xenografts tumour models, respectively.
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: 1. Hatzivassiliou, G., Haling, J. R., Chen, H., Song, K., Price, S., Heald, R., Hewitt, J. F., Zak, M., Peck, A., Orr, C., Merchant, M., Hoeflich, K. P., Chan, J., Luoh, S. M., Anderson, D. J., Ludlam, M. J., Wiesmann, C., Ultsch, M., Friedman, L. S., Malek, S. and Belvin, M. (2013) Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers. Nature. 501, 232-236 2. Zaanan, A., Okamoto, K., Kawakami, H., Khazaie, K., Huang, S. and Sinicrope, F. A. (2015) The Mutant KRAS Gene Up-regulates BCL-XL Protein via STAT3 to Confer Apoptosis Resistance That Is Reversed by BIM Protein Induction and BCL-XL Antagonism. J Biol Chem. 290, 23838-23849

Biological Activity

Description	GDC-0623 is a potent and ATP-uncompetitive inhibitor of MEK1 with Ki value of 0.13 nM.
Targets	MEK1
IC50	0.13 nM (Ki)

Quality Control

Quality Control & MSDS

View current batch:

Purity = 98.30%

Chemical structure

GDC-0623

mRNA synthesis

Tyramide Signal Amplification (TSA)

Phos Binding Reagent Acrylamide

Cell Counting Kit-8 (CCK-8)

Inhibitor Cocktails

Background

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Chemical Properties

Protocol

Biological Activity

Quality Control

Quality Control & MSDS

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