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    GDC-0623 (G-868)
    GDC-0623 (G-868)

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0451
    CAS #: 1168091-68-6Purity ≥98%

    Description: GDC-0623 (G868) is a novel, potent, orally bioactive, selective and non-ATP-competitive (allosteric) inhibitor of MEK1 with potential anticancer activity. It inhibits MEK1 with a Ki of 0.13 nM. GDC-0623 is effective against both mutant BRAF and mutant KRAS. It induces the dimerization of MEK and stabilizes the RAF–MEK complex. MEK plays a key role in the RAS/RAF/MEK/ERK signaling pathway that regulates cell growth and the constitutive activation of this pathway has been implicated in many cancers.

    References: Nature. 2013 Sep 12;501(7466):232-6; J Biol Chem. 2015 Sep 25;290(39):23838-49.

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    Molecular Weight (MW)456.21
    FormulaC16H14FIN4O3
    CAS No.1168091-68-6
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 91 mg/mL (199.5 mM)
    Water: <1 mg/mL
    Ethanol: 5 mg/mL (11.00 mM)
    Solubility (In vivo)Methylcellulose 0.1% tween 80 0.1% (MCT): 5 mg/mL
    Synonyms

    G-868; GDC 0623; G868; GDC 0632; GDC0632; G 868;

    Chemical Name: 5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide

    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)

    SMILES Code: O=C(C1=C(NC2=CC=C(I)C=C2F)N3C(C=C1)=CN=C3)NOCCO 


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    In Vitro

    In vitro activity: In a panel of mutant cancer cell lines, GDC-0623 inhibits cellular proliferation with EC50 of 4 nM, 53 nM, 11 nM, 18 nM and 94 nM for A375 (BRAFV600E), HCT116 (KRASG13D), COLO 205 (V600E), HT-29 (V600E), and HCT116 (G13D) cells, respectively. In isogenic KRAS HCT116 and mutant KRAS SW620 colon cells, GDC-0623 upregulates BIM via its loss of phosphorylation at Ser69. GDC-0623 plus ABT-263 induces a synergistic cell apoptosis.


    Kinase Assay: 0.14 μM of purified inactive recombinant MEK-1 (Upstate) 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 Assay: Flag-MEK1 mutants, S212P and S212A, are generated using the QuickChange site directed mutagenesis kit. Mammalian expression vectors for N-terminal Flag tagged MEK-1 are expressed in HCT116 cells. 1.8×106 HCT116 cells are plated in 10 cm plate and transfected on the following day with 17 μg of expression constructs using lipofectamine 2000. After 48 hours cells are treated with inhibitors for the indicated times, harvested and lysed in 100 μL cell extraction buffer. Cell lysates from each sample are analyzed by SDS-PAGE. Membranes are incubated with phospho-MEK S221, phospho-ERK1/2 and MEK1 primary antibodies and immunoreactive proteins are analyzed by SuperSignal West Pico Chemiluminescent Substrate. 

    In VivoIn vivo, GDC-0623 (40 mg/kg, p.o.) causes potent tumor growth inhibition (TGI) in mouse MiaPaCa-2 (120%), A375 (102%) and HCT116 (115%) xenografts.
    Animal modelMice bearing MiaPaCa-2, A375 and HCT116 xenografts
    Formulation & DosageFormulated in  Methylcellulose 0.1% tween 80 0.1% (MCT); 40 mg/kg; p.o.
    ReferencesNature. 2013 Sep 12;501(7466):232-6; J Biol Chem. 2015 Sep 25;290(39):23838-49.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    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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