Discovery of 7-Methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5 -yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a Potent and Selective First-in-Class Inhibitor of Protein Kinase R (PKR)-like Endoplasmic Reticulum Kinase (PERK)

Oncology Research, Protein Dynamics DPU, GlaxoSmithKline Research and Development, Collegeville, Pennsylvania 19426, United States.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 07/2012; 55(16):7193-207. DOI: 10.1021/jm300713s
Source: PubMed


Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. Evidence that PERK is implicated in tumorigenesis and cancer cell survival stimulated our search for small molecule inhibitors. Through screening and lead optimization using the human PERK crystal structure, we discovered compound 38 (GSK2606414), an orally available, potent, and selective PERK inhibitor. Compound 38 inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice.

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    • "Challenging questions in the future are how we can determine the eIF2α kinase that is central to these detrimental mechanisms at different AD stages and whether inhibiting a single eIF2α kinase may be sufficient to exert beneficial effects in clinical settings. Currently, selective and bioavailable inhibitors of PERK (Axten et al., 2012; Moreno et al., 2013) and PKR (Couturier et al., 2010, 2012) are developed for neurodegenerative disease therapy, although their potential adverse effects (e.g., hyperglycemia with PERK inhibitors) need to be carefully addressed. Clearly, much work remains for validation and practical application, but the present data warrant further preclinical evaluations of the eIF2α kinase inhibitors in animal models (e.g., the regimen for timing and duration of drug administration to optimize their efficacies during neuropathological development) as novel disease-modifying therapeutic interventions to treat AD and related cognitive impairments. "
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    ABSTRACT: Cell signaling in response to an array of diverse stress stimuli converges on the phosphorylation of eukaryotic initiation factor-2α (eIF2α). Evidence is accumulating that persistent eIF2α phosphorylation at Ser51 through prolonged overactivation of regulatory kinases occurs in neurodegenerative diseases such as Alzheimer's disease (AD), leading to shutdown of general translation and translational activation of a subset of mRNAs. Recent advances in the development of gene-based strategies and bioavailable inhibitors, which specifically target one of the eIF2α kinases, have enabled us to investigate pathogenic roles of dysregulated eIF2α phosphorylation pathways. This review provides an overview of animal model studies in this field, focusing particularly on molecular mechanisms by which the dysregulation of eIF2α kinases may account for synaptic and memory deficits associated with AD. A growing body of evidence suggests that correcting aberrant eIF2α kinase activities may serve as disease-modifying therapeutic interventions to treat AD and related cognitive disorders.
    Full-text · Article · Apr 2014 · Frontiers in Molecular Neuroscience
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    • "Also, other studies provided evidence that the antioxidant functions of PERK may also be mediated independent of eIF2α phosphorylation through the activation of the transcription factor Nrf2.28 How the ATP-competitive inhibitors selectively inhibit some but not all of PERK functions is not known, but this effect could be related to the ability of the drugs to trap the kinase in an inactive conformation rather than inhibiting its phosphotransfer activity.17 Also, the drugs inhibit the activity of several other kinases at high concentrations,17 a property that could contribute to the induction of PERK-independent effects in response to ER stress. Furthermore, PERK may not be the dominant kinase that phosphorylates eIF2α in different tumor types, and as such, pharmacological inhibition of the kinase may not be sufficient to impair eIF2α phosphorylation because of compensation by other eIF2α kinases.13 "
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    ABSTRACT: 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 α 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-eIF2α 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 eIF2α phosphorylation. Also, GSK2656157 does not always mimic the biological effects of the genetic inactivation of PERK. Furthermore, cells treated with GSK2656157 increase eIF2α phosphorylation as a means to compensate for the loss of PERK. Using human tumor cells impaired in eIF2α phosphorylation, we demonstrate that GSK2656157 increases ER stress-mediated death suggesting that the drug acts independent of inhibition of eIF2α 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 eIF2α phosphorylation.
    Full-text · Article · Jan 2014 · Cell cycle (Georgetown, Tex.)
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    • "In a recent study, Axten et al., [73] screened a proprietary collection of kinase inhibitors for PERK inhibition and found thienopyrimidine (Fig. 7a) with an IC 50 of 11 nM using a kinase assay. The assay uses GSTePERK kinase domain and biotinylated His-tagged full length recombinant human eIF-2a substrate. "
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    ABSTRACT: Eukaryotic initiation factor 2 alpha kinases (eIF-2α kinases) are key mediators of stress response in cells. In mammalian cells, there are four eIF-2α kinases, namely HRI (Heme Regulated Inhibitor), PKR (RNA-dependent Protein Kinase), PERK (PKR-like ER Kinase) and GCN2 (General Control Non-derepressible 2). These kinases get activated during diverse cytoplasmic stress conditions and phosphorylate the alpha-subunit of eIF2, leading to global protein synthesis inhibition. Therefore, eIF-2α kinases play a vital role in various cellular processes such as proliferation, differentiation, apoptosis and cell signaling. Deregulation of eIF-2α kinases and protein synthesis has been linked to numerous pathological conditions such as certain cancers, anemia and neurodegenerative disorders. Thus, modulation of these kinases by small molecules holds a great therapeutic promise. In this review we have compiled the available information on inhibitors and activators of these four eIF-2α kinases. The review concludes with a note on the selectivity issue of currently available modulators and future perspectives for the design of specific small molecule probes.
    Full-text · Article · Aug 2013 · Biochimie
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