UPR (unfolded protein response), dysregulation of which has been implicated in many important pathologies, is an essential pathway to cope with ER stress. PERK is one of three primary effectors of the UPR. It can be activated by the released ER chaperones caused by increase of unfolded proteins in the ER and thus phosphorylates eIF2α. GSK2606414 is a potent and selective PERK inhibitor with IC50 value of 0.4nM (measured by cytoplasmic PERK domain phosphorylation of EIF2α). Treatment with GSK2606414 at concentration ranging in 0.03-0.3μM for 2h can significantly inhibit p-PERK induced by 1μM thapsigargin with IC50 value<0.03μM in A549 cells. Oral administration of GSK2606414 at dose of 50mg/kg and 150mg/kg, b.i.d., for 21 days showed antitumor activity in a human pancreatic tumor xenograft model[1].
作用机制
The trifluoromethyl meta-substituent of GSK2606414 can occupy the PERK kinase domain.[1]
GSK2606414 细胞实验
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.
Diabetes. 2015 Nov;64(11):3951-62.
PDAC cells
10μM
0–72 h
GSK2606414 significantly inhibited the cell viability of BZW1 high expression organoids
Gastroenterology. 2022 Apr;162(4):1256-1271.e14.
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
Cell Death Dis. 2020 May 12;11(5):360.
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.
Redox Biol. 2021 Oct;46:102115.
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
Cell Death Dis. 2020 Oct 13;11(10):847.
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.
Mol Ther Oncolytics. 2020 Jan 17;16:238-249.
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.
Mol Ther Oncolytics. 2020 Jan 17;16:238-249.
GSK2606414 动物实验
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
Gastroenterology. 2022 Apr;162(4):1256-1271.e14.
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
Cell Death Dis. 2020 Oct 13;11(10):847.
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.
Inhibition of thapsigargin-induced autophosphorylation of PERK in human A549 cells after 2 hrs by Western blotting
22827572
human A549 cells
0.03 μM
Function assay
2 h
Inhibition of thapsigargin-induced autophosphorylation of PERK in human A549 cells at 0.03 uM after 2 hrs by Western blotting
22827572
human A549 cells
Function assay
1 h
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
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