GDC-0623 (G-868)

Alias: G-868; GDC 0623; G868; GDC 0632; GDC0632; G 868
Cat No.:V0451 Purity: ≥98%
GDC-0623 (G868) is a novel, potent, orally bioactive, selective and non-ATP-competitive (allosteric) inhibitor of MEK1 with potential anticancer activity.
GDC-0623 (G-868) Chemical Structure CAS No.: 1168091-68-6
Product category: MEK
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

GDC-0623 (G868) is a novel, potent, orally bioactive, selective, and non-ATP-competitive (allosteric) MEK1 inhibitor that may have anticancer effects. With a Ki of 0.13 nM, it blocks MEK1. Both mutant BRAF and mutant KRAS can be effectively treated with GDC-0623. The RAF-MEK complex is stabilized and MEK is made to dimerize. The RAS/RAF/MEK/ERK signaling pathway, which controls cell growth, is important for MEK activity, and constitutive activation of this pathway has been linked to numerous cancers.

Biological Activity I Assay Protocols (From Reference)
Targets
MEK1 (Ki = 0.13 nM)
ln Vitro
GDC-0623 (RG 7421) and G-573 are able to prevent MEK phosphorylation by CRAF in vitro, and able to block MEK phosphorylation by BRAF(V600E)[1]. Although GDC-0623 (RG 7421) is a powerful, ATP-uncompetitive MEK1 inhibitor, it exhibits distinct changes in cellular activity when compared to the other two inhibitors, with only a 6-fold reduction in EC50[2].
ln Vivo
GDC-0623 (RG 7421) (40 mg/kg, p.o.) exhibits %TGI, or percent tumour growth inhibitionin MiaPaCa-2 xenograft model. In all three KRAS models, GDC-0623 (RG 7421) and G-573 exhibit stronger antitumor activity than GDC-0623 (RG 7421)[1].
Enzyme Assay
In 15 μL of kinase buffer (20 mM MOPS pH 7.2, 25 mM beta glycerol phosphate, 5 mM EGTA, 1 mM sodium orthovanadate, 1 mM DTT, 100 μM ATP, 15 mM MgCl2), 0.14 μM of purified inactive recombinant MEK-1 (Upstate) protein is preincubated with inhibitors. 1 ng of BRAF, CRAF, or BRAF V600E is added to the reaction in a total volume of 20 μL after 10 minutes of incubation at 30°C. Also added are 0.5 μg of inactive recombinant ERK2. The reaction is stopped by adding Laemmle sample buffer following a 30-minute incubation period at 30°C. SDS-PAGE analysis of the level of phosphor-MEK provides an indication of the enzyme activity. SuperSignal West Pico Chemiluminescent Substrate allows the visualization of immunoreactive proteins.
Cell Assay
The QuickChange site-directed mutagenesis kit is used to produce the S212P and S212A mutants of Flag-MEK1. HCT116 cells express N-terminally Flag-tagged MEK-1 from mammalian expression vectors. The following day, 1.8×106 HCT116 cells are plated in a 10 cm plate and lipofectamine 2000 is used to transfect the cells with 17 g of expression constructs. After 48 hours, cells are harvested and lysed in 100 L cell extraction buffer after being treated with inhibitors for the indicated times. SDS-PAGE is used to examine the cell lysates from each sample. Immunoreactive proteins are examined using SuperSignal West Pico Chemiluminescent Substrate after membranes have been incubated with phospho-MEK S221, phospho-ERK1/2, and phospho-MEK1 primary antibodies.
Animal Protocol
Colo205 xenografts are created by injecting 6–8 week old female nude (nu/nu) mice with 5×106 cells resuspended in Hank's Balanced Salt Solution (HBSS) subcutaneously (s.c.) into the rear right flank. In order to create NCI-H2122 xenografts, 6–8 week old female nu/nu mice are injected with 1×107 cells that have been resuspended in Hank's Balanced Salt Solution (HBSS) and matrigel (growth factor reduced). In order to start an A375 or MiaPaca-2 xenograft, 1 mm3 tumor fragments from the corresponding passaged tumors are injected subcutaneously (s.c.) into the flank of athymic nu/nu mice. When tumors have grown to approximately 200 mm3, mice are randomized and treated with either vehicle (methylcellulose 0.1% tween 80 0.1% (MCT)), GDC-0973 (at 10 mg/kg), GDC-0623 (RG 7421) (at 40 mg/kg), or G-573 (at 100 mg/kg). All MEK inhibitor doses corresponded to maximally tolerated doses (MTDs), which did not cause weight loss of more than 15% to 20% of body weight. Using digital calipers and the equation (L×W×W)/2, tumor volumes are calculated. Tumor growth inhibition (%TGI) is calculated as a proportion of the area under the fitted curve (AUC) for the corresponding dose group daily in comparison to the vehicle. Animal weights are measured twice a week, and mice are taken out of the study if they lose ≥20% or more of their body weight. Complete responses (CRs) are defined as any tumor demonstrating a 100% reduction in tumor volume at any point during the study, whereas partial responses (PRs) are defined as any tumor demonstrating a ≥ 50% decrease in tumor volume.
References

[1]. Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers. Nature. 2013 Sep 12;501(7466):232-6.

[2]. Elucidating the Mechanisms of Formation for Two Unusual Cytochrome P450-Mediated Fused Ring Metabolites of GDC-0623, a MAPK/ERK Kinase Inhibitor. Drug Metab Dispos. 2015 Dec;43(12):1929-1933.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C16H14FIN4O3
Molecular Weight
456.21
Exact Mass
456.01
Elemental Analysis
C, 42.12; H, 3.09; F, 4.16; I, 27.82; N, 12.28; O, 10.52
CAS #
1168091-68-6
Appearance
Solid powder
SMILES
C1=CC(=C(C=C1I)F)NC2=C(C=CC3=CN=CN32)C(=O)NOCCO
InChi Key
RFWVETIZUQEJEF-UHFFFAOYSA-N
InChi Code
InChI=1S/C16H14FIN4O3/c17-13-7-10(18)1-4-14(13)20-15-12(16(24)21-25-6-5-23)3-2-11-8-19-9-22(11)15/h1-4,7-9,20,23H,5-6H2,(H,21,24)
Chemical Name
5-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide
Synonyms
G-868; GDC 0623; G868; GDC 0632; GDC0632; G 868
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: ~91 mg/mL (~199.5 mM)
Water: <1 mg/mL
Ethanol: ~5 mg/mL(~11.0 mM)
Solubility (In Vivo)
Methylcellulose 0.1% tween 80 0.1% (MCT): 5mg/mL
 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.1920 mL 10.9599 mL 21.9197 mL
5 mM 0.4384 mL 2.1920 mL 4.3839 mL
10 mM 0.2192 mL 1.0960 mL 2.1920 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.

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Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
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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.

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Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT01106599 Completed Drug: GDC-0623 Solid Cancers Genentech, Inc. April 2010 Phase 1
Biological Data
  • GDC-0623

    BIM regulates apoptosis induction by the combination of GDC-0623 and ABT-263 via a mechanism involving the release of BIM from BCL-XL protein. J Biol Chem. 2015 Sep 25; 290(39): 23838–23849.

  • GDC-0623

    Proposed mechanisms for the formation of M14 and M13 from GDC-0623 and M15.2015 Dec;43(12):1929-33.

  • GDC-0623

    MS/MS spectra (collision-induced dissociation of MH+ions) and proposed product ions for GDC-0623 and its metabolites under study.2015 Dec;43(12):1929-33.

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