GDC-0623-RG-7421-DataSheet-生命科學試劑-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEGDC-0623Cat. No.: HY-15610CAS No.: 1168091-68-6Synonyms: RG 7421; MEK inhibitor 1分式: CHFINO分量: 456.21作靶點: MEK作通路: MAPK/ERK Pathway儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實驗 DMSO : 30 mg/mL (6

2、5.76 mM)* means soluble, but saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制備儲備液1 mM 2.1920 mL 10.9599 mL 21.9197 mL5 mM 0.4384 mL 2.1920 mL 4.3839 mL10 mM 0.2192 mL 1.0960 mL 2.1920 mL請根據(jù)產(chǎn)品在不同溶劑中的溶解度，選擇合適的溶劑配制儲備液，并請注意儲備液的保存式和期限。BIOLOGICAL ACTIVITY物活性 GDC-0623 (RG 7421)種有效的，ATP 競爭性的 ME

3、K1 抑制劑，Ki值為 0.13 nM，對 HCT116 細胞中 KRAS(G13D)的 EC50 值為 42 nM，對 A375 細胞中 BRAFV600E的 EC50 值為 7 nM。IC50 & Target MEK10.13 nM (Ki, +ATP)1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemE體外研究 GDC-0623 (RG 7421) and G-573 are able to prevent MEK phosphorylation by CRAF in vitro, and able toblock MEK phosphor

4、ylation by BRAF(V600E) 1. GDC-0623 (RG 7421) is potent, ATP-uncompetitiveinhibitors of MEK1 but shows distinct shifts in cellular activity compared with the other two inhibitors, only 6-fold half-maximum effective concentration (EC50) decreases 2.體內(nèi)研究 GDC-0623 (RG 7421) (40 mg/kg, p.o.) shows percen

5、t tumour growth inhibition (%TGI) in MiaPaCa-2xenograft model. GDC-0623 (RG 7421) and G-573 show superior antitumour activity compared to GDC-0623(RG 7421) in all three KRAS models 1.PROTOCOLCell Assay 1 Flag-MEK1 mutants, S212P and S212A, are generated using the QuickChange site directed mutagenesi

6、s kit.Mammalian expression vectors for N-terminal Flag tagged MEK-1 are expressed in HCT116 cells. 1.8106HCT116 cells are plated in 10 cm plate and transfected on the following day with 17 g of expressionconstructs using lipofectamine 2000. After 48 hours cells are treated with inhibitors for the in

7、dicated times,harvested and lysed in 100 L cell extraction buffer. Cell lysates from each sample are analyzed by SDS. Membranes are incubated with phospho-MEK S221, phospho-ERK1/2 and MEK1 primary antibodiesand immunoreactive proteins are analyzed by SuperSignal West Pico Chemiluminescent Substrate.

8、MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Colo205 xenografts are established by inoculating 5106 cells resuspended in Hanks Balanced Salt SolutionAdministration 1 (HBSS) subcutaneously (s.c.) in the rear right flank of 6-8 week old female n

9、ude (nu/nu) mice. NCI-H2122xenografts are established by inoculating 1107 cells resuspended in Hanks Balanced Salt Solution (HBSS)plus matrigel (growth factor reduced) s.c. in the rear right flank of 6-8 week old female nu/nu mice. Both A375and MiaPaca-2 xenografts are initiated by transplanting 1 m

10、m3 tumor fragments from their respectivepassaged tumors s.c. into the flank of athymic nu/nu mice. When tumors reached appr 200 mm3, mice arerandomized and treated with daily (QD) oral gavage (PO) with either vehicle methylcellulose 0.1% tween 800.1% (MCT), GDC-0973 (at 10 mg/kg), GDC-0623 (RG 7421)

11、 (40 mg/kg), or G-573 (100 mg/kg). All dosesof MEK inhibitors represented maximal tolerated doses (MTDs), resulting in no more than 15-20% bodyweight loss. Tumor volumes are determined using digital calipers using the formula (LWW)/2. Tumorgrowth inhibition (%TGI) iscalculated as the percentage of t

12、he area under the fitted curve (AUC) for therespective dose group per day in relation to the vehicle. Animal weights are recorded twice per week andmice are removed from study if body weights dropped 20%. Partial responses (PRs) are defined as anytumor demonstrating a 50% decrease in tumor volume, w

13、hereas complete responses (CRs) are defined asany tumor demonstrating 100% reduction in tumor volume at any point during the study.MCE has not independently confirmed the accuracy of these methods. They are for reference only.戶使本產(chǎn)品發(fā)表的科研獻 Sci Transl Med. 2018 Jul 18;10(450). pii: eaaq1093. Sci Signal

14、. 2018 Oct 30;11(554). pii: eaar6795. Cancers (Basel). 2019 Feb 1;11(2). pii: E164.2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemE bioRxiv. December 6, 2017. Patent. US20170326205A1.See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Hatzivassiliou G, et al. Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers. Nature. 2013Sep 12;501(7466):232-6.2. Takahashi RH, et al. Elucidating the Mechanisms of Formation for Two Unusual Cytochrome P450-Mediated Fused Ring Metabolites ofGDC-0623, a MAPK/ERK Kinase Inhibitor. Drug Metab Dispos. 20