Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma

Papandreou, Ioanna; Denko, Nicholas C.; Olson, Michael F.; Melckebeke, Heleen Van; Lust, Sofie; Tam, Arvin B.; Solow-Cordero, David E.; Bouley, Donna M.; Offner, Fritz; Niwa, Maho; Koong, Albert C.

doi:10.1182/blood-2010-08-303099

Cited by 425 publications

(415 citation statements)

References 16 publications

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“…S1 A-E). Both of these drugs were used at concentrations that do not compromise cell viability or induce any other toxicity (21,34,35,(37)(38)(39)(40). Consistent with earlier reports, these IRE1 inhibitors had no effect on the kinase function of IRE1 (Fig.…”

Section: Resultssupporting

confidence: 75%

“…4A). Although limited pharmacodynamic data are available for the IRE1 inhibitors that we used, target engagement has been shown in cells and tissues (21,39). We based our in vivo drug dosage and delivery on earlier in vivo studies that successfully administered the IRE1 modulators without toxicity (21,24,31).…”

Section: Resultsmentioning

confidence: 99%

“…The action of both compounds is wellunderstood mechanistically. Both form a Schiff base with a specific lysine positioned in the active site of the IRE1 RNase domain, blocking its function, and both show no overt toxicity when administered systemically (21,32,33). Thus, we reasoned that these drugs might have therapeutic applicability in atherosclerosis.…”

mentioning

confidence: 99%

“…This quest has led to the identification of several new small molecules that target the enzymatic activities of specific UPR regulators (19)(20)(21)(22)(23). Specifically, blocking IRE1 or XBP1s function has been shown to be beneficial for restraining tumor progression in mouse models (21,24), highlighting that the specific targeting of the UPR can have beneficial impact in disease.…”

mentioning

confidence: 99%

“…Third, experimentally sustained Xbp1 mRNA splicing in the vessel wall promotes atherosclerosis, whereas its ablation ameliorates hypercholesterolemia in obese or apolipoprotein E-deficient (ApoE −/− ) mice (10,30). Two small molecules, STF-083010 and 4μ8C, which selectively inhibit IRE1's RNase function, have been used in cells and animals to produce favorable therapeutic outcomes in other disease settings: STF-083010 reduced growth of multiple myeloma (21,24,31,32), and 4μ8c suppressed inflammation in a murine arthritis model (33). The action of both compounds is wellunderstood mechanistically.…”

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confidence: 99%

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Targeting IRE1 with small molecules counteracts progression of atherosclerosis

Tufanlı

Telkoparan-Akillilar

Acosta‐Alvear

et al. 2017

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

174

195

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Metaflammation, an atypical, metabolically induced, chronic lowgrade inflammation, plays an important role in the development of obesity, diabetes, and atherosclerosis. An important primer for metaflammation is the persistent metabolic overloading of the endoplasmic reticulum (ER), leading to its functional impairment. Activation of the unfolded protein response (UPR), a homeostatic regulatory network that responds to ER stress, is a hallmark of all stages of atherosclerotic plaque formation. The most conserved ERresident UPR regulator, the kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1), is activated in lipid-laden macrophages that infiltrate the atherosclerotic lesions. Using RNA sequencing in macrophages, we discovered that IRE1 regulates the expression of many proatherogenic genes, including several important cytokines and chemokines. We show that IRE1 inhibitors uncouple lipid-induced ER stress from inflammasome activation in both mouse and human macrophages. In vivo, these IRE1 inhibitors led to a significant decrease in hyperlipidemia-induced IL-1β and IL-18 production, lowered T-helper type-1 immune responses, and reduced atherosclerotic plaque size without altering the plasma lipid profiles in apolipoprotein E-deficient mice. These results show that pharmacologic modulation of IRE1 counteracts metaflammation and alleviates atherosclerosis.endoplasmic reticulum stress | unfolded protein response | metaflammation | lipotoxicity | atherosclerosis C omplex molecular interactions between environment, diet, and genetics that take place at the metabolic and immune interface provoke a low-grade, chronic inflammatory responsemetaflammation-that engages cells of the immune system (macrophages, neutrophils, and lymphocytes) and metabolic tissues (adipocytes, hepatocytes, and pancreatic cells) (1). An important primer for metaflammation is chronic metabolic overloading of organelles, such as the endoplasmic reticulum (ER) and mitochondria, which results in impairment of their functions (2).The ER serves essential cellular functions that include the synthesis and folding of secreted and transmembrane proteins, calcium storage, and lipid synthesis for membrane biogenesis or energy storage. Disruption of any of these functions leads to ER stress and the subsequent activation of an elaborate network of adaptive responses, collectively known as the unfolded protein response (UPR) (3). The UPR reestablishes homeostasis through both transcriptional and translational layers of control. The UPR signals through three mechanistically distinct branches that are initiated by the ER-resident protein folding sensors inositolrequiring enzyme 1 (IRE1), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) (3).IRE1 controls the phylogenetically most conserved branch of the UPR found from fungi to metazoans. It has an ER-lumenal sensor domain that recognizes unfolded peptides and cytosolic kinase and endoribonuclease (RNase) domains that relay the information to downstrea...

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Section: Resultssupporting

confidence: 75%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Targeting IRE1 with small molecules counteracts progression of atherosclerosis

Tufanlı

Telkoparan-Akillilar

Acosta‐Alvear

et al. 2017

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

174

195

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Negative feedback and modern anti‐cancer strategies targeting the ER stress response

2020

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Endoplasmic reticulum (ER) stress is a cell state in which misfolded or unfolded proteins are aberrantly accumulated in the ER. ER stress induces an evolutionarily conserved adaptive response, named the ER stress response, that deploys a self-regulated machinery to maintain cellular proteostasis. However, compared to its well-established canonical activation mechanism, the negative feedback mechanisms regulating the ER stress response remain unclear and no accepted methods or markers have been established. Several studies have documented that both endogenous and exogenous insults can induce ER stress in cancer. Based on this evidence, small molecule inhibitors targeting ER stress response have been designed to kill cancer cells, with some of them showing excellent curative effects. Here, we review recent advances in our understanding of negative feedback of the ER stress response and compare the markers used to date. We also summarize therapeutic inhibitors targeting ER stress response and highlight the promises and challenges ahead.

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Multiple Myeloma

Bianchi¹,

Anderson²

2015

Targeted Therapy in Translational Cancer Research

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Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma

Cited by 425 publications

References 16 publications

Targeting IRE1 with small molecules counteracts progression of atherosclerosis

Targeting IRE1 with small molecules counteracts progression of atherosclerosis

Negative feedback and modern anti‐cancer strategies targeting the ER stress response

Multiple Myeloma

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