GSK2656157

GSK2656157 is a highly selective inhibitor of protein kinase R-like ER kinase (PERK) with IC50 value of 0.9nM [1].

GSK2656157 is highly selective for PERK enzyme against a panel of 300 kinases. In the BxPC3 pancreatic tumor cell line, treatment of GSK2656157 causes an inhibition of PERK and decreases in the downstream substrates, including phospho-eIF2α, ATF4 and CHOP. The inhibition of PERK results in effects on de novo protein synthesis as shown in BxPC3 cells [1].

In vivo assay shows that a single 50 mg/kg oral dose of GSK2656157 can completely inhibit the Thr980 phosphorylation of endogenous pancreatic PERK in mice. Furthermore, GSK2656157 causes dose-dependent inhibition of tumor growth in human tumor xenograft models of pancreatic cancer (BxPC3, HPAC and Capan2) and multiple myeloma (NCI-H929). Among these cancers, the Capan2 tumor is most sensitive [1].

References:
[1] Atkins C, Liu Q, Minthorn E, Zhang SY, Figueroa DJ, Moss K, Stanley TB, Sanders B, Goetz A, Gaul N, Choudhry AE, Alsaid H, Jucker BM, Axten JM, Kumar R. Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res. 2013 Mar 15;73(6):1993-2002.

Evidence for eIF2alpha phosphorylation-independent effects of GSK2656157, a novel catalytic inhibitor of PERK with clinical implications.[Pubmed:24401334]

Cell Cycle. 2014;13(5):801-6.

The endoplasmic reticulum (ER)-resident protein kinase PERK is a major component of the unfolded protein response (UPR), which promotes the adaptation of cells to various forms of stress. PERK phosphorylates the alpha subunit of the translation initiation factor eIF2 at serine 51, a modification that plays a key role in the regulation of mRNA translation in stressed cells. Several studies have demonstrated that the PERK-eIF2alpha phosphorylation pathway maintains insulin biosynthesis and glucose homeostasis, facilitates tumor formation and decreases the efficacy of tumor treatment with chemotherapeutic drugs. Recently, a selective catalytic PERK inhibitor termed GSK2656157 has been developed with anti-tumor properties in mice. Herein, we provide evidence that inhibition of PERK activity by GSK2656157 does not always correlate with inhibition of eIF2alpha phosphorylation. Also, GSK2656157 does not always mimic the biological effects of the genetic inactivation of PERK. Furthermore, cells treated with GSK2656157 increase eIF2alpha phosphorylation as a means to compensate for the loss of PERK. Using human tumor cells impaired in eIF2alpha phosphorylation, we demonstrate that GSK2656157 induces ER stress-mediated death suggesting that the drug acts independent of the inhibition of eIF2alpha phosphorylation. We conclude that GSK2656157 might be a useful compound to dissect pathways that compensate for the loss of PERK and/or identify PERK pathways that are independent of eIF2alpha phosphorylation.

GSK2656157, a PERK inhibitor, reduced LPS-induced IL-1beta production through inhibiting Caspase 1 activation in macrophage-like J774.1 cells.[Pubmed:27251848]

Immunopharmacol Immunotoxicol. 2016 Aug;38(4):298-302.

IL-1beta is one of the inflammatory cytokines and is cleaved from pro-IL-1beta proteolytically by activated Caspase 1. For the activation of Caspase 1, inflammasome was formed by two signals, what is called, priming and triggering signals. In this study, it was found that mouse macrophage J774.1 cells, when treated by single large amount of lipopolysaccharide (LPS), produced a significant amount of IL-1beta. On the other hand, IL-1beta production was not detected when treated by a single, small amount of LPS. Then, focusing on endoplasmic reticulum (ER) stress response among stress responses induced by a large amount of LPS, when GSK2656157, a PERK inhibitor, was used for inhibition of ER stress, GSK2656157 reduced IL-1beta production dose-dependently. Next, when Thapsigargin, an ER stress reagent, was added with LPS, IL-1beta production increased more than by LPS alone. Thus, these results suggested that ER stress was involved in LPS-induced IL-1beta production. When the activation of Caspase 1 was examined by fluorescence activated cell sorter analysis, it was found that GSK2656157 inhibited LPS-induced Caspase 1 activation. Further, it was confirmed that GSK2656157 did not affect LPS-induced TNF-alpha production and activation of NF-kappaB and specifically inhibited the PERK/eIF-2alpha pathway. Therefore, it was found that GSK2656157 specifically inhibited ER stress induced by large amount of LPS and reduced LPS-induced IL-1beta production through inhibition of Caspase 1 activation.

Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development.[Pubmed:24900593]

ACS Med Chem Lett. 2013 Aug 12;4(10):964-8.

We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), which inhibited PERK activation in cells and demonstrated tumor growth inhibition in a human tumor xenograft in mice. In continuation of our drug discovery program, we applied a strategy to decrease inhibitor lipophilicity as a means to improve physical properties and pharmacokinetics. This report describes our medicinal chemistry optimization culminating in the discovery of the PERK inhibitor GSK2656157 (6), which was selected for advancement to preclinical development.

GSK2656157 is a selective and ATP-competitive inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) with an IC50 of 0.9 nM.

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