product name GDC-0623
Description: GDC-0623 is a potent and ATP-uncompetitive (allosteric) MEK1 inhibitor with Ki of 0.13 nM. GDC-0623 has efficacy against both mutant BRAF and mutant KRAS.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.
References: Nature. 2013 Sep 12;501(7466):232-6; J Biol Chem. 2015 Sep 25;290(39):23838-49.
456.21
Formula
C16H14FIN4O3
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
other peoduct :
| 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: |
|---|---|
| In Vivo | In 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 model | Mice bearing MiaPaCa-2, A375 and HCT116 xenografts |
| Formulation & Dosage | Formulated in Methylcellulose 0.1% tween 80 0.1% (MCT); 40 mg/kg; p.o. |
| References | Nature. 2013 Sep 12;501(7466):232-6; J Biol Chem. 2015 Sep 25;290(39):23838-49. |
