PERK Inhibitor II, GSK2656157-Calbiochem

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一般描述

A cell-permeable pyrrolopyrimidinamine compound that acts as a potent, ATP-competitive EIF2AK3/PERK inhibitor (IC₅₀= 0.9 nM; [ATP] = 10 ?M), displaying ≥511-fold selectivity over HRI/EIF2AK1, BRK, PKR/EIF2AK2, and MEKK2 (IC₅₀= 460, 822, 905, and 954 nM, respectively) and much reduced or little activity toward more than 300 other kinases. Potently prevents ER stress-induced enhancement of PERK and eIF2α phosphorylation as well as ATF4 & CHOP upregulation in human BxPC3 and murine LL/2 culturesin vitro(IC₅₀≤30 nM; 1 h drug preincubation prior to 6 h 1 ?M Thapsigargin treatment, Cat. No. 586005) and exhibits antitumor efficacy against 3 pancreas and 1 multiple myeloma xenografts in mice (54-110% tumor growth inhibition; 150 mg/kg/12 h via p.o.)in vivo. More selective than GSK2606414 (Cat. No. 516535).
A cell-permeable pyrrolopyrimidinamine compound that acts as a potent, ATP-competitive EIF2AK3/PERK inhibitor (IC₅₀= 0.9 nM; [ATP] = 10 ?M), displaying ≥511-fold selectivity over HRI/EIF2AK1, BRK, PKR/EIF2AK2, and MEKK2 (IC₅₀= 460, 822, 905, and 954 nM, respectively) and much reduced or little activity toward more than 300 other kinases. While GSK2656157 potently inhibits ER stress-induced enhancement of PERK and eIF2α phosphorylation as well as ATF4 & CHOP upregulation in human PxBC3 and murine LL/2 culturesin vitro(IC₅₀≤30 nM; 1 h drug preincubation prior to 6 h ER-stress induction by 1 ?M Thapsigargin, Cat. No. 586005), only basal PERK phosphorylation, but not basal eIF2α phosphorylation or ATF4 & CHOP expression, is seen inhibited in pancreas (by >95% up to 8 h post single 50 mg/kg oral dose) and tumor tissues upon GSK2656157 administration in micein vivo, resulting in the observed antitumor efficacy (54-110% tumor growth inhibition; 150 mg/kg/12 h via p.o.) and reversible pancreas damage (44% and 95% of control pancreas mass, respectively, 1 d and 15 d post 14 d 150 mg/kg/12 h oral dosing). Comparing to its structural analog GSK2606414 (Cat. No. 516535), GSK2656157 exhibits much reduced potency toward Aurora B, MLK2/MAP3K10, MLCK2/MYLK2, c-MER (IC₅₀= 1.259, 2.796, 3.039, and 3.431 ?M, respectively), c-Kit, and DDR2 (69.84% and 25.41% inhibition, respectively, at 10 ?M)

生化/生理作用

Cell permeable: yes
Primary Target
PERK
Reversible: yes

包装

Packaged under inert gas

警告

Toxicity: Regulatory Review (Z)

重悬

Use only fresh DMSO for reconstitution.
Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

其他说明

Atkins, C., et al. 2013.Cancer Res.73,1993.

法律信息

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

基本信息

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