GSK2606414

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.

GSK2606414 Chemical Structure

GSK2606414 Chemical Structure

CAS: 1337531-36-8

Selleck's GSK2606414 has been cited by 84 publications

Purity & Quality Control

Batch: Purity: 99.92%
99.92

GSK2606414 Related Products

Choose Selective PERK Inhibitors

Cell Data

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
L929 Anti-neprotic assay Anti-neprotic activity in mouse L929 cells assessed as reduction in TNF-induced necroptosis and measured every 1 hr by SYTOX Green dye based fluorescence assay, IC50=0.0004μM. 31622096
MEF Anti-neprotic assay Anti-neprotic activity in mouse MEF cells assessed as reduction in TNF-induced necroptosis and measured every 1 hr in presence of z-VAD by SYTOX Green dye based fluorescence assay, IC50=0.0073μM. 31622096
A549 Function assay 2 hrs Inhibition of thapsigargin-induced autophosphorylation of PERK in human A549 cells after 2 hrs by Western blotting, IC50<0.03μM. 22827572
A549 Function assay 1 hr Inhibition of thapsigargin-induced autophosphorylation of PERK in human A549 cells preincubated for 1 hr followed by thapsigargin-induction measured after 1 hr by Western blotting analysis, IC50<0.03μM. 24900593
A549 Function assay 0.03 uM 2 hrs Inhibition of thapsigargin-induced autophosphorylation of PERK in human A549 cells at 0.03 uM after 2 hrs by Western blotting 22827572
Caco-2 Function assay 48 hours Determination of IC50 values for inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells after 48 hours by high content imaging, IC50=0.25μM. ChEMBL
Click to View More Cell Line Experimental Data

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.
Features The first PERK-selective inhibitor with good oral bioavailability and crosses the blood-brain barrier.
Targets
EIF2AK3 (PERK) [1]
(Cell-free assay)
0.4 nM
In vitro
In vitro

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

Kinase Assay 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 Research 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.

Experimental Result Images Methods Biomarkers Images PMID
Western blot p-PERK / PERK p-KIT / KIT / p-STAT5 / p-ERK 28332979
In Vivo
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]

Animal Research Animal Models BxPC3 human pancreatic xenograft model
Dosages ~150 mg/kg
Administration Oral administration

Chemical Information & Solubility

Molecular Weight 451.44 Formula

C24H20F3N5O

CAS No. 1337531-36-8 SDF Download GSK2606414 SDF
Smiles CN1C=C(C2=C(N=CN=C21)N)C3=CC4=C(C=C3)N(CC4)C(=O)CC5=CC(=CC=C5)C(F)(F)F
Storage (From the date of receipt)

In vitro
Batch:

DMSO : 90 mg/mL ( (199.36 mM); Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Ethanol : 19 mg/mL

Water : Insoluble


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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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