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Chemical Structure| 1337531-36-8 Chemical Structure| 1337531-36-8

Structure of GSK2606414
CAS No.: 1337531-36-8

Chemical Structure| 1337531-36-8

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GSK2606414 is an orally available, potent, and selective PERK inhibitor with an IC50 of 0.4 nM.

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Product Citations

Product Citations

Chen, Long ; Shi, Yiping ; Xiao, Danrui ; Huang, Yijie ; Jiang, Yangjing ; Liang, Min , et al.

Abstract: Rupture of vulnerable carotid atherosclerotic plaque is one of the leading causes of ischemic stroke. However, the mechanisms driving the transition from stable to vulnerable plaques have not yet been elucidated. NR4A1 is an orphan nuclear receptor that functions in various inflammatory diseases. To explore the role of NR4A1 in vulnerable plaque formation, we generated a vulnerable plaque mouse model by combining partial ligation of the left common carotid artery and left renal artery in ApoE−/− and ApoE−/−;NR4A1−/− mice. Our research revealed that NR4A1 deficiency significantly worsened the pathology of vulnerable plaque, increasing intraplaque hemorrhage, rupture with thrombus, and the occurrence of multilayer with discontinuity. Moreover, NR4A1 deficiency exacerbated macrophage infiltration, inflammation, and oxidative stress. Mechanistically, we identified Bcat1 as the target of NR4A1. NR4A1 modulated the integrated stress response (ISR) in macrophages by transcriptionally inhibiting Bcat1, thus influencing the progression of vulnerable plaque. ISR inhibitor GSK2606414 or Bcat1 inhibitor ERG240 significantly ameliorated atherosclerotic plaque formation and increased plaque stability. Notably, supplementation with Celastrol, an herbal extract, stabilized atherosclerotic plaques in mice. These findings suggest that NR4A1 deficiency exacerbates vulnerable plaque by activating ISR via targeting Bcat1. The NR4A1/Bcat1/ISR axis is therefore an important therapeutic target for stabilizing atherosclerotic plaque.

Keywords: NR4A1 ; Integrated stress response ; Vulnerable plaque ; Bcat1

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Product Details of GSK2606414

CAS No. :1337531-36-8
Formula : C24H20F3N5O
M.W : 451.44
SMILES Code : FC(C1=CC(CC(N2CCC3=C2C=CC(C4=CN(C)C5=NC=NC(N)=C54)=C3)=O)=CC=C1)(F)F
MDL No. :MFCD25976926
InChI Key :SIXVRXARNAVBTC-UHFFFAOYSA-N
Pubchem ID :53469448

Safety of GSK2606414

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302
Precautionary Statements:P280-P305+P351+P338

Isoform Comparison

Biological Activity

Target
  • PERK

    EIF2AK3 (PERK), IC50:0.4 nM

In Vitro:

Cell Line
Concentration Treated Time Description References
INS-1E cells 0.5 μM To investigate the effect of GSK2606414 on ER stress-induced PPP1R15B expression, results showed that GSK2606414 prevented the induction of PPP1R15B expression. PMC4713904
PDAC cells 10μM 0–72 h GSK2606414 significantly inhibited the cell viability of BZW1 high expression organoids PMC9436032
pancreatic cancer cells T3M-4 250 nM 4 h To investigate the effect of GSK2606414 on mitochondrial morphology induced by ER stress, results showed that GSK2606414 partially reversed mitochondrial morphology in Sc cells PMC7217954
mouse vascular smooth muscle cell (VSMC) 2 μM 24 h GSK2606414 inhibited TMAO-induced ROS generation, indicating that PERK plays a crucial role in TMAO-enhanced Ang II responses. PMC8408632
Bone marrow-derived macrophages (BMMs) 0.01, 0.05, 0.1 μM 4 days GSK2606414 significantly inhibited osteoclast formation and bone resorption function, and reduced the number of F-actin rings PMC7554039
FaDu cells 2 μM and 5 μM 72 h GSK2606414 enhanced the efficacy of reovirus in FaDu cells, as evidenced by significantly reduced cell viability. PMC7047134
HN5 cells 2 μM and 5 μM 72 h GSK2606414 enhanced the efficacy of reovirus in HN5 cells, as evidenced by significantly reduced cell viability. PMC7047134

In Vivo:

Species
Animal Model
Administration Dosage Frequency Description References
nude mice subcutaneous xenograft model oral 100mg/kg twice a week, until after tumor development GSK2606414 significantly suppressed tumor growth and prolonged the survival time of nude mice PMC9436032
Mice Ovariectomy model (OVX) Intragastric gavage 50 mg/kg Every 2 days for 6 weeks GSK2606414 significantly alleviated bone loss in OVX mice and inhibited osteoclast formation PMC7554039
NSG mice HN5 cell subcutaneous xenograft model Oral 50 mg/kg Once daily for 5 days, followed by 2 days off, repeated for 3 cycles GSK2606414 significantly enhanced the antitumor efficacy of reovirus in the HN5 cell xenograft model, as evidenced by a significant reduction in tumor volume. PMC7047134

Protocol

Bio Calculators
Preparing Stock Solutions 1mg 5mg 10mg

1 mM

5 mM

10 mM

2.22mL

0.44mL

0.22mL

11.08mL

2.22mL

1.11mL

22.15mL

4.43mL

2.22mL

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