GSK2606414

Catalog No.S7307 Batch:S730703

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Technical Data

Formula

C24H20F3N5O

Molecular Weight 451.44 CAS No. 1337531-36-8
Solubility (25°C)* In vitro DMSO 90 mg/mL (199.36 mM)
Ethanol 21 mg/mL (46.51 mM)
Water Insoluble
In vivo (Add solvents to the product individually and in order)
Clear solution
5% DMSO 95% Corn oil
0.9mg/ml Taking the 1 mL working solution as an example, add 50 μL of 18 mg/ml clear DMSO stock solution to 950 μL of corn oil and mix evenly. The mixed solution should be used immediately for optimal results. 
Clear solution
5% DMSO 45% PEG 300 ddH2O
1.0mg/ml Taking the 1 mL working solution as an example, add 50 μL of 20 mg/ml clarified DMSO stock solution to 450 μL PEG 300, mix evenly to clarify it; then continue to add 500 μL ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results. 
Clear solution
5%DMSO 40%PEG300 5%Tween80 50%ddH2O
10.0mg/ml Taking the 1 mL working solution as an example, add 50 μL of 200 mg/ml clarified DMSO stock solution to 400 μL of PEG300, mix evenly to clarify it; add 50 μL of Tween80 to the above system, mix evenly to clarify; then continue to add 500 μL of ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results. 
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

Preparing Stock Solutions

Biological Activity

Description GSK2606414 is an orally available, potent, and selective PERK inhibitor with IC50 of 0.4 nM, displaying at least 100-fold selectivity over the other EIF2AKs assayed. GSK2606414 impairs GANT-61 induced autophagy in NB cells with MYCN amplification. GSK2606414 exacerbates ER stress-induced apoptosis in HCT116 cells while reduces the apoptosis in SIL1 KD HeLa cells.
Targets
EIF2AK3 (PERK) [1]
(Cell-free assay)
0.4 nM
In vitro

GSK2606414 inhibits PERK Autophosphorylation in A459 Cells with IC50 of <0.3 μM. [1]

In vivo

GSK2606414 exhibits high oral availability, and low to moderate blood clearance in mouse, rat, and dog. GSK2606414, administered orally, inhibits tumor growth in a dose-dependent manner in mice bearing pancreatic human BxPC3 tumors. [1]

Features The first PERK-selective inhibitor with good oral bioavailability and crosses the blood-brain barrier.

Protocol (from reference)

Kinase Assay:

[1]

  • PKR-like Endoplasmic Reticulum Kinase (PERK) Assay (HTRF Format)

    GST-PERK cytoplasmic domain is purchased. 6-His-full-length human eIF2α is purified from baculovirus expression in Sf9 insect cells. The eIF2α protein is buffer exchanged by dialysis into PBS, chemically modified by NHS-LC-biotin and then buffer exchanged by dialysis into 50 mM Tris, pH 7.2, 250 mM NaCl, 5 mM DTT. Protein is aliquoted and stored at −80 °C. Quench solution is freshly prepared and when added to the reaction gives final concentrations of 4 nM eIF2α phospho-ser51-antibody, 4 nM Eu-1024 labeled anti-rabbit IgG, 40 nM streptavidin Surelight APC, and 15 mM EDTA. Reactions were performed in black 384-well polystyrene low volume plates in a final volume of 10 μL. The reaction volume contains, in final concentrations, 10 mM HEPES, 5 mM MgCl2, 5 μM ATP, 1 mM DTT, 2 mM CHAPS, 40 nM biotinylated 6-His-eIF2α, and 0.4 nM GST-PERK. Compounds under analysis are dissolved in DMSO to 1.0 mM and serially diluted 1–3 with DMSO through 11 dilutions. An amount of 0.1 μL of each concentration is transferred to the corresponding well of an assay plate. This creates a final compound concentration range from 0.00017 to 10 μM. GST-PERK solution is added to assay plates containing compounds and preincubated for 30 min at room temperature. The reaction is initiated by the addition of ATP and eIF2α substrate solution. After 1 h of incubation, the quench solution is added. The plates are covered for 2 h at room temperature prior to determination of signal. The resulting signal is quantified on a Viewlux reader. The APC signal is normalized to the europium signal by transforming the data through an APC/Eu calculation. The data for concentration response curves are plotted as % inhibition calculated with the data reduction formula 100 × [1 – (U1 – C2)/(C1 – C2)] versus concentration of compound where U is the unknown value, C1 is the average control value obtained for 1% DMSO, and C2 is the average control value obtained for 0.1 M EDTA. Data are fitted with a curve described by where A is the minimum response, B is the maximum response, D is the slope factor, x is the concentration of the compound, and C is the IC50. The results for each compound are recorded as IC50 values.

Cell Assay:

[1]

  • Cell lines

    A549 cells

  • Concentrations

    0.3 μM

  • Incubation Time

    2 h

  • Method

    Cells were incubated with PERK inhibitor (GSK2606414, compound 38) and then stimulated with thapsigargin. After 2 h, the cells were lysed and analyzed for inhibition of PERK autophosphorylation.

Animal Study:

[1]

  • Animal Models

    BxPC3 human pancreatic xenograft model

  • Dosages

    ~150 mg/kg

  • Administration

    Oral administration

Customer Product Validation

, , Mol Neurobiol, 2016, 54(3):1808-1817

Data from [Data independently produced by , , J Neurosci, 2018, 38(9):2372-2384]

Data from [Data independently produced by , , J Clin Endocrinol Metab, 2017, 102(2):634-643]

Data from [Data independently produced by , , Sci Rep, 2016, 6:32929]

Selleck's GSK2606414 has been cited by 93 publications

The ribotoxic stress response drives UV-mediated cell death [ Cell, 2024, 187(14):3652-3670.e40] PubMed: 38843833
MANF facilitates breast cancer cell survival under glucose-starvation conditions via PRKN-mediated mitophagy regulation [ Autophagy, 2024, 1-22.] PubMed: 39147386
Nucleus pulposus cells regulate macrophages in degenerated intervertebral discs via the integrated stress response-mediated CCL2/7-CCR2 signaling pathway [ Exp Mol Med, 2024, 56(2):408-421.] PubMed: 38316963
RACK1 promotes autophagy via the PERK signaling pathway to protect against traumatic brain injury in rats [ CNS Neurosci Ther, 2024, 30(3):e14691] PubMed: 38532543
Integrated stress response (ISR) activation and apoptosis through HRI kinase by PG3 and other p53 pathway-restoring cancer therapeutics [ Oncotarget, 2024, 15:614-633] PubMed: 39288289
Sevoflurane Exposure Induces Neuronal Cell Ferroptosis Initiated by Increase of Intracellular Hydrogen Peroxide in the Developing Brain via ER Stress ATF3 Activation [ Mol Neurobiol, 2024, 61(4):2313-2335] PubMed: 37874483
A RIPK3-independent role of MLKL in suppressing parthanatos promotes immune evasion in hepatocellular carcinoma [ Cell Discov, 2023, 9(1):7] PubMed: 36650126
Nitric oxide-induced ribosome collision activates ribosomal surveillance mechanisms [ Cell Death Dis, 2023, 14(7):467] PubMed: 37495584
Nitric oxide-induced ribosome collision activates ribosomal surveillance mechanisms [ Cell Death Dis, 2023, 14(7):467] PubMed: 37495584
IRE1α arm of unfolded protein response in muscle-specific TGF-β signaling-mediated regulation of muscle cell immunological properties [ Cell Mol Biol Lett, 2023, 28(1):15] PubMed: 36849929

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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