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. GSK2656157 is a potent and selective PERK inhibitor with IC50 value of 0.9nM on PERK enzyme activity, highly selective for PERK with IC50 values >100nM against a panel of 300 kinases. Pretreatment with GSK2656157 at concentration ranging in 10-30nM resulted in block of UPR activated by thapsigargin or tunicamycin, including autophosphorylation of PERK and its downstream substrates as p-eIF2α, ATF4 and CHOP in BxPC3 cells. The transcription of a series of tunicamycin-induced UPR gene was attenuated by 1μM GSK2656157 in the same cell line, including CHOP, HERP, ERO1LB, DNAJB9, SEL1L, etc.. Complete inhibition of pPERK-Thr980 can be observed through 8h after a single oral dose of 50mg/kg GSK2656157 In vivo, which showed the pharmacokinetic properties of this compound, without effect on p-eIF2α-S51 level. Oral dose of 50mg/kg or 150mg/kg GSK2656157 twice daily resulted in varying degrees of tumor growth inhibition in mice bearing various human tumor xenografts, including by 61% tumor growth inhibition in BxPC3 pancreas xenografts, by 47% and 65% in NCI-H929 multiple myeloma xenografts, by 31% and 54% in HPAC pancreas xenografts and by 107% and 114% in Capan2 pancreas xenografts. After treatment with 50mg/kg or 150mg/kg GSK2656157 for 3 weeks, a decrease in blood vessel density in tumors can be observed in BxPC3 tumor-bearing mice[1].
作用机制
GSK2656157 is an ATP-competitive PERK inhibitor.[1]
GSK2656157 细胞研究
细胞系
浓度
检测类型
检测时间
活动说明
数据源
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, IC50=0.03 μM
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=0.03 μM
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