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Purity: ≥98%
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.
| Targets |
MEK1 (Ki = 0.13 nM)
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| 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].
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| 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].
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| 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.
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| 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.
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| 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.
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| References |
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| Additional Infomation |
GDC-0623 is a member of the class of imidazopyridines that is imidazo[1,5-a]pyridine substituted by (2-fluoro-4-iodophenyl)amino and (2-hydroxyethoxy)aminoacyl groups at positions 5 and 6. It is a potent ATP non-competitive inhibitor of MEK1 (Ki = 0.13nM) and also has efficacy against both mutant BRAF and mutant KRAS. It is in clinical development for treatment of patients with locally advanced or metastatic solid tumors. It has a role as an EC 2.7.12.2 (mitogen-activated protein kinase kinase) inhibitor, an antineoplastic agent and an apoptosis inducer. It is a substituted aniline, a member of monofluorobenzenes, an organoiodine compound, an imidazopyridine, a secondary amino compound, a hydroxamic acid ester and a primary alcohol.
GDC-0623 has been used in trials studying the treatment of Solid Cancers. MEK Inhibitor GDC-0623 is an orally active, selective MEK inhibitor with potential antineoplastic activity. MEK inhibitor GDC-0623 specifically inhibits mitogen-activated protein kinase kinase (MEK or MAP/ERK kinase), resulting in inhibition of growth factor-mediated cell signaling and tumor cell proliferation. MEK is a key component of the RAS/RAF/MEK/ERK signaling pathway that regulates cell growth; constitutive activation of this pathway has been implicated in many cancers. |
| Molecular Formula |
C16H14FIN4O3
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|---|---|---|
| Molecular Weight |
456.21
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| Exact Mass |
456.009
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| Elemental Analysis |
C, 42.12; H, 3.09; F, 4.16; I, 27.82; N, 12.28; O, 10.52
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| CAS # |
1168091-68-6
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| Related CAS # |
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| PubChem CID |
42642654
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| Appearance |
Light yellow to gray solid powder
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| Density |
1.8±0.1 g/cm3
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| Index of Refraction |
1.703
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| LogP |
4.16
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
25
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| Complexity |
461
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| Defined Atom Stereocenter Count |
0
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| SMILES |
IC1C=CC(=C(C=1)F)NC1=C(C(NOCCO)=O)C=CC2=CN=CN12
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| InChi Key |
RFWVETIZUQEJEF-UHFFFAOYSA-N
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| 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)
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| Chemical Name |
5-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide
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| Synonyms |
G-868; GDC 0623; G868; GDC 0632; GDC0632; G 868
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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 (5.48 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 (5.48 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 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: Methylcellulose 0.1% tween 80 0.1% (MCT): 5mg/mL |
| 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.
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 |
| NCT01106599 | Completed | Drug: GDC-0623 | Solid Cancers | Genentech, Inc. | April 2010 | Phase 1 |
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. |
Proposed mechanisms for the formation of M14 and M13 from GDC-0623 and M15.Drug Metab Dispos.2015 Dec;43(12):1929-33. |
MS/MS spectra (collision-induced dissociation of MH+ions) and proposed product ions for GDC-0623 and its metabolites under study.Drug Metab Dispos.2015 Dec;43(12):1929-33. |
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