Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development

Axten, Jeffrey M.; Romeril, Stuart P.; Shu, Arthur Y. L.; Ralph, Jeffrey M.; Medina, Jesús R.; Feng, Yuping; Li, William Hoi Hong; Grant, Steven; Heerding, Dirk A.; Minthorn, Elisabeth A.; Mencken, Thomas; Gaul, Nathan; Goetz, Aaron S.; Stanley, Thomas B.; Hassell, Annie M.; Gampe, Robert T.; Atkins, Charity; Kumar, Rakesh

doi:10.1021/ml400228e

Cited by 190 publications

(172 citation statements)

References 21 publications

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“…for neutralizing IFNAR1 in patients with diverse inflammatory/ autoimmune syndromes (61,62). Our data suggest that a similar strategy could be potentially envisioned for relieving IFN-mediated pancreatotoxicity in patients with Wolcott-Rallison or patients who receive PERK inhibitors for treating tumors (22)(23)(24) and prion-mediated neurogenerative disorders (25).…”

Section: Discussionmentioning

confidence: 85%

See 1 more Smart Citation

Type I interferons mediate pancreatic toxicities of PERK inhibition

Yu¹,

Zhao²,

Gui³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The great preclinical promise of the pancreatic endoplasmic reticulum kinase (PERK) inhibitors in neurodegenerative disorders and cancers is marred by pancreatic injury and diabetic syndrome observed in PERK knockout mice and humans lacking PERK function and suffering from Wolcott-Rallison syndrome. PERK mediates many of the unfolded protein response (UPR)-induced events, including degradation of the type 1 interferon (IFN) receptor IFNAR1 in vitro. Here we report that whole-body or pancreas-specific Perk ablation in mice leads to an increase in IFNAR1 protein levels and signaling in pancreatic tissues. Concurrent IFNAR1 deletion attenuated the loss of PERKdeficient exocrine and endocrine pancreatic tissues and prevented the development of diabetes. Experiments using pancreas-specific Perk knockouts, bone marrow transplantation, and cultured pancreatic islets demonstrated that stabilization of IFNAR1 and the ensuing increased IFN signaling in pancreatic tissues represents a major driver of injury triggered by Perk loss. Neutralization of IFNAR1 prevented pancreatic toxicity of PERK inhibitor, indicating that blocking the IFN pathway can mitigate human genetic disorders associated with PERK deficiency and help the clinical use of PERK inhibitors.T umor microenvironment-associated deficit in oxygen and nutrients activate numerous pathways that aid cancer and tumor stroma cells by increasing their ability to survive, withstand anticancer therapies, and ultimately select for more aggressive and viable clones capable of metastasizing (1). Activation of the unfolded protein response (UPR) plays a central role in these processes (2). Three branches of this response include stimulation of activating transcription factor-6 and activation of two kinases, inositol requiring enzyme 1α/β and the eukaryotic translation initiation factor 2-alpha kinase 3 [also termed double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase, or pancreatic endoplasmic reticulum kinase (PERK)]. The latter kinase contributes to phosphorylation of the eukaryotic translation initiation factor 2-alpha and controls the rate of global translation and noncanonical induction of specific proteins that help cope with stress (reviewed in ref. 2).Among three main UPR pathways, signaling through PERK has received the most attention for its central role in cancer (3-6). Genetic studies have demonstrated that PERK is essential in supporting tumor growth and progression via diverse mechanisms, including stimulation of angiogenesis (7-12), potential effects on antitumor immunity (13,14), and direct increase in cancer cell viability by altering its metabolic status (15), promoting survival autophagy (16-18), and induction of prosurvival microRNAs (19). Accordingly, development of novel, potent, and selective PERK inhibitors as a means to treat cancers has been proposed (20, 21). Several PERK inhibitors have shown promising results in various preclinical tumor models (22-24). Furthermore, some of these inhibitors can protect against the prion-...

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Section: Discussionmentioning

confidence: 85%

“…Accordingly, development of novel, potent, and selective PERK inhibitors as a means to treat cancers has been proposed (20,21). Several PERK inhibitors have shown promising results in various preclinical tumor models (22)(23)(24). Furthermore, some of these inhibitors can protect against the prion-mediated neurogenerative disorders (25).…”

mentioning

confidence: 99%

Type I interferons mediate pancreatic toxicities of PERK inhibition

Yu¹,

Zhao²,

Gui³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…GSK2656157 is a recently described inhibitor of protein kinase R-like ER kinase (PERK), which senses misfolded proteins and initiates a response to ER stress. 63 Guanabenz is an inhibitor of the protein phosphatase 1 regulatory subunit GADD34, which allows normal cellular functions to recommence once the stressor has been resolved. 64 We assessed the effects of GSK2656157 and guanabenz on oligodendrocyte cultures from control NC2 and PLP1 mutants PMD2 and PMD10.…”

Section: Mobilization Of Plp1 Into Oligodendrocyte Processes By Smallmentioning

confidence: 99%

Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes

Nevin

Factor

Karl

et al. 2017

The American Journal of Human Genetics

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Pelizaeus-Merzbacher disease (PMD) is a pediatric disease of myelin in the central nervous system and manifests with a wide spectrum of clinical severities. Although PMD is a rare monogenic disease, hundreds of mutations in the X-linked myelin gene proteolipid protein 1 (PLP1) have been identified in humans. Attempts to identify a common pathogenic process underlying PMD have been complicated by an incomplete understanding of PLP1 dysfunction and limited access to primary human oligodendrocytes. To address this, we generated panels of human induced pluripotent stem cells (hiPSCs) and hiPSC-derived oligodendrocytes from 12 individuals with mutations spanning the genetic and clinical diversity of PMD-including point mutations and duplication, triplication, and deletion of PLP1-and developed an in vitro platform for molecular and cellular characterization of all 12 mutations simultaneously. We identified individual and shared defects in PLP1 mRNA expression and splicing, oligodendrocyte progenitor development, and oligodendrocyte morphology and capacity for myelination. These observations enabled classification of PMD subgroups by cell-intrinsic phenotypes and identified a subset of mutations for targeted testing of small-molecule modulators of the endoplasmic reticulum stress response, which improved both morphologic and myelination defects. Collectively, these data provide insights into the pathogeneses of a variety of PLP1 mutations and suggest that disparate etiologies of PMD could require specific treatment approaches for subsets of individuals. More broadly, this study demonstrates the versatility of a hiPSC-based panel spanning the mutational heterogeneity within a single disease and establishes a widely applicable platform for genotype-phenotype correlation and drug screening in any human myelin disorder.

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“…For example, GSK2656157, a small-molecule inhibitor of PERK kinase, displays anti-angiogenic and anti-tumoral activity toward pancreatic adenocarcinoma-derived tumor xenografts (Atkins et al, 2013;Axten et al, 2013). Correspondingly, dynamic contrast-enhanced MRI of GSK2656157-treated tumors revealed lower perfusion rates and a reduction in the expression of the endothelial cell marker vanWillebrand factor (vWF) (Atkins et al, 2013).…”

Section: Therapeutic Modulation Of the Upr For Pathological Angiogenesismentioning

confidence: 99%

ER Stress and Angiogenesis

2015

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Proper tissue vascularization is vital for cellular function as it delivers oxygen, nutrients, hormones, and immune cells and helps to clear cellular debris and metabolic waste products. Tissue angiogenesis occurs to satisfy energy requirements and cellular sensors of metabolic imbalance coordinate vessel growth. In this regard, the classical pathways of the unfolded protein response activated under conditions of ER stress have recently been described to generate angiomodulatory or angiostatic signals. This review elaborates on the link between angiogenesis and ER stress and discusses the implications for diseases characterized by altered vascular homeostasis, such as cancer, retinopathies, and atherosclerosis.

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Discovery of GSK2656157: An Optimized PERK Inhibitor Selected for Preclinical Development

Cited by 190 publications

References 21 publications

Type I interferons mediate pancreatic toxicities of PERK inhibition

Type I interferons mediate pancreatic toxicities of PERK inhibition

Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes

ER Stress and Angiogenesis

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