GSK2656157 - PERK 抑制剂 - 生命科学试剂 - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEGSK2656157Cat. No.: HY-13820CAS No.: 1337532-29-2分式: CHFNO分量: 416.45作靶点: PERK; Autophagy作通路: Cell Cycle/DNA Damage; Autophagy储存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性数据体外实验 DMSO : 41 mg/mL (98.45

2、mM)* means soluble, but saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制备储备液1 mM 2.4012 mL 12.0062 mL 24.0125 mL5 mM 0.4802 mL 2.4012 mL 4.8025 mL10 mM 0.2401 mL 1.2006 mL 2.4012 mL请根据产品在不同溶剂中的溶解度，选择合适的溶剂配制储备液，并请注意储备液的保存式和期限。体内实验请根据您的实验动物和给药式选择适当的溶解案，配制前请先配制澄清的储备液，再依次添加助溶剂(为保证实验结果的可靠性，体

3、内实验的作液，建议您现现配，当天使；澄清的储备液可以根据储存条件，适当保存；以下溶剂前的百分 指该溶剂在您配制终溶液中的体积占)：1. 请依序添加每种溶剂： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 0.5 mg/mL (1.20 mM); Clear solution2. 请依序添加每种溶剂： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 0.5 mg/mL (1.20 mM); Clear solution3. 请依序添加每种溶剂： 10% DMSO 90% corn oil1

4、/4 Master of Small Molecules 您边的抑制剂师www.MedChemESolubility: 0.5 mg/mL (1.20 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 GSK2656157是选择性，ATP竞争性的 PERK 抑制剂，IC50 值为 0.9 nM。IC50 & Target EIF2AK3 (PERK) EIF2AK1 (HRI) BRK EIF2AK2 (PKR)0.9 nM (IC50) 460 nM (IC50) 905 nM (IC50) 905 nM (IC50)MEKK3 Aurora B KHS L

5、CK954 nM (IC50) 1259 nM (IC50) 1764 nM (IC50) 2344 nM (IC50)MLK2 MEKK3 ALK5 MLCK22796 nM (IC50) 2847 nM (IC50) 3020 nM (IC50) 3039 nM (IC50)EIF2AK4(GCN2) c-MER PI3K WNK33162 nM (IC50) 3431 nM (IC50) 3802 nM (IC50) 5951 nM (IC50)LRRK2 ROCK1 MSK1 NEK16918 nM (IC50) 7244 nM (IC50) 8985 nM (IC50) 9807 n

6、M (IC50)AXL JAK29808 nM (IC50) 24547 nM (IC50)体外研究 GSK2656157 results in inhibition of PERK activation as well as decreases in the downstream substrates,phospho-eIF2, ATF4, and CHOP with an IC50 in the range of 10-30 nM in the BxPC3 pancreatic tumor cellline. Cells that are exposed to 1 M GSK2656157

7、 before UPR induction are able to block this effect on denovo protein synthesis 1. GSK2656157 causes the activation of another eIF2 kinase to compensate for theloss of PERK activity in HT1080 cells. GSK2656157 inhibits the growth of the HT1080 cells 2. GSK2656157inhibits LPS-induced IL-1 production,

8、 LPS-induced Caspase 1 activation and LPS-induced eIF-2phosphorylation, but does not inhibit LPS-induced TNF- production 3.体内研究 GSK2656157 (1.5-150 mg/kg, p.o.) results in dose-dependent inhibition of phospho-PERK Thr980, with morethan 80% inhibition at 50 and 150 mg/kg. GSK2656157 (50-150 mg/kg, p.

9、o.) results in dose-dependentinhibition of tumor growth in human tumor xenograft models 1.PROTOCOLKinase Assay 1 BxPC3 (human pancreatic adenocarcinoma) or LL/2 (murine lung carcinoma) cells are treated with DMSO orvarious concentrations of GSK2656157 for 1 hour, followed by addition of 5 g/mL tunic

10、amycin or 1 Mthapsigargin for an additional 6 hours to induce endoplasmic reticulum-stress. Cells are lysed in coldradioimmunoprecipitation assay (RIPA) buffer 150 mM NaCl, 50 mM Tris-Cl pH 7.5, 0.25% sodiumdeoxycholate, 1% NP-40, protease inhibitors, and 100 mM sodium orthovanadate. Clarified lysat

11、es are2/4 Master of Small Molecules 您边的抑制剂师www.MedChemEresolved by SDSand transferred to nitrocellulose membrane using NuPAGE system. Blots areincubated with antibodies to total PERK, p-eIF-2 Ser51, total eIF-2, ATF4, and CHOP. IRDye700DX-labeled goat anti-mouse immunoglobulin G (IgG), IRDye800-CW d

12、onkey anti-goat IgG, and IRDye800-CWgoat anti-rabbit IgG are used as secondary antibodies. Proteins are detected on the Odyssey InfraredImager.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Cell Assay 1 BxPC3 cells are treated with DMSO or 1 M GSK26561

13、57 for 1 hour before adding 5 g/mL tunicamycin foran additional hour. Cells are metabolically labeled with 125 Ci 35S-methionine for the subsequent 1 hour.Cells are lysed in cold RIPA buffer and lysates are resolved by SDS, followed by exposure to aphosphorimager screen. Control cells are also pretr

14、eated with 100 M cyclohexamide for 1 hour followed bymetabolic labeling. Radioisotope incorporation is quantitated using ImageQuant 5.2 software.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Exponentially growing HPAC (5106 cells/mouse), Capan-

15、2 (10106 cells/mouse), or NCI-H929 (16Administration 1 cells/mouse) cells are implanted subcutaneously into the right flank of 8- to 12-week-old female SCID mice.Similarly, 10106 BxPC3 cells per mouse are implanted in female nude mice. When the tumors reachedapproximately 200 mm3 in size, the animal

16、s are weighed, and block randomized according to tumor size intotreatment groups of 8 mice each. Mice are dosed orally with the formulating vehicle or GSK2656157. Miceare weighed and tumors measured by calipers twice weekly. Tumor volumes are calculated. The percentageof tumor growth inhibition is c

17、alculated on each day of tumor measurement using the formula: 100 1 (average growth of the compound-treated tumors/average growth of vehicle-treated control tumors).MCE has not independently confirmed the accuracy of these methods. They are for reference only.户使本产品发表的科研献 J Neuroinflammation. 2017 Ma

18、y 11;14(1):104. Int J Mol Sci. 2017 Apr 18;18(4). pii: E854. Cancer Cell Int. 2017 Jan 10;17:12. Vascul Pharmacol. 2018 Oct;109:36-44. Brain Res Bull. 2019 Mar;146:28-39.See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Atkins C, et al. Characterization of a novel PERK kinase inh

19、ibitor with antitumor and antiangiogenic activity. Cancer Res. 2013 Mar15;73(6):1993-2002.2. Krishnamoorthy J, et al. Evidence for eIF2 phosphorylation-independent effects of GSK2656157, a novel catalytic inhibitor of PERKwith clinical implications. Cell Cycle. 2014 Mar 1;13(5):801-6.3. Ando T, et al. GSK2656157, a PERK i