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更新于：2025-05-07

EN460

更新于：2025-05-07

概要

概要

基本信息

药物类型

小分子化药

别名

靶点

ERO1L

作用方式

抑制剂

作用机制

ERO1L 抑制剂(endoplasmic reticulum oxidoreductase 1 alpha inhibitors)

治疗领域-

在研适应症-

非在研适应症-

原研机构

New York University School of Medicine

在研机构

New York University School of Medicine

非在研机构-

权益机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构/序列

分子式C22H12ClF3N2O4

InChIKeyRSLFQCNAOMQAIH-UHFFFAOYSA-N

CAS号496807-64-8

关联

100 项与 EN460 相关的临床结果

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100 项与 EN460 相关的转化医学

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100 项与 EN460 相关的专利（医药）

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项与 EN460 相关的文献（医药）

2024-11-01·Progress in Neurobiology

ERO1A inhibition mitigates neuronal ER stress and ameliorates UBQLN2ALS phenotypes in Drosophila melanogaster

Article

作者: Sangphukieo, Apiwat ; Yeewa, Ranchana ; Jantaree, Phatcharida ; Wongkummool, Wasinee ; Lo Piccolo, Luca ; Poompouang, Siwat ; Piccolo, Luca Lo ; Chaiyawat, Parunya ; Jantrapirom, Salinee ; Yamsri, Titaree

Modulating the ER stress pathway holds therapeutic promise for neurodegenerative diseases; however, identifying optimal targets remains challenging. In this study, we conducted an unbiased screening to systematically search for commonly up-regulated proteins in ER stress-related neurodegenerative conditions, with endoplasmic reticulum oxidoreductase 1 alpha (ERO1A) emerging as a significant hit. Further experiments conducted in the model organism Drosophila melanogaster demonstrated that elevated levels of Drosophila ERO1A (ERO1L) were indeed detrimental to neurons. Conversely, genetic suppression or pharmacological inhibition of ERO1L activity provided neuroprotection under ER stress and extended the lifespan of flies. To translate these findings, we performed a genetic modifier screening and underscored significant neuroprotective effects against UBQLN2^ALS pathology. Additionally, administration of the chemical probe inhibitor of ERO1A, known as EN460, enhanced locomotive functions and neuromuscular junction (NMJ) morphology in Drosophila UBQLN2^ALS model. Mechanistically, targeting ERO1L during environmental or pathological ER stress mitigated proteotoxic stress by lowering either the PERK or IRE1 branches of the unfolded protein response (UPR). These findings suggest ERO1A as a promising therapeutic target in UBQLN2^ALS and other ER stress-related conditions.

2023-03-01·Environmental Toxicology and Pharmacology

Arsenite enhances ERO1α expression via ryanodine receptor dependent and independent mechanisms

Article

作者: Guidarelli, Andrea ; Zito, Ester ; Spina, Andrea ; Cantoni, Orazio ; Fiorani, Mara

Arsenite is a potent carcinogen and toxic compound inducing an array of deleterious effects via different mechanisms, which include the Ca²⁺-dependent formation of reactive oxygen species. The mechanism whereby the metalloid affects Ca²⁺ homeostasis involves an initial stimulation of the inositol 1, 4, 5-triphosphate receptor, an event associated with an endoplasmic reticulum (ER) stress leading to increased ERO1α expression, and ERO1α dependent activation of the ryanodine receptor (RyR). Ca²⁺ release from the RyR is then critically connected with the mitochondrial accumulation of Ca²⁺. We now report that the resulting formation of mitochondrial superoxide triggers a second mechanism of ER stress dependent ERO1α expression, which however fails to impact on Ca²⁺ release from the RyR or, more generally, on Ca²⁺ homeostasis. Our results therefore demonstrate that arsenite stimulates two different and sequential mechanisms leading to increased ERO1α expression with different functions, possibly due to their different subcellular compartmentalization.

2023-01-01·Cell Reports

The endoplasmic reticulum kinase PERK interacts with the oxidoreductase ERO1 to metabolically adapt mitochondria

Article

作者: Ballanyi, Klaus ; Zito, Ester ; Gibhardt, Christine Silvia ; Gutiérrez, Tomas ; Hario, Saaya ; Moses, Audric ; Lemieux, Hélène ; Bhat, Rakesh ; Moore, Jack ; Takahashi-Yamashiro, Kei ; Yap, Megan C ; Chen, Junsheng ; Mina, Lucas ; Campbell, Robert E ; Sitia, Roberto ; Mast, Heather ; Le, Giang N T ; Nasu, Yusuke ; Simmen, Thomas ; Bogeski, Ivan ; Bassot, Arthur

Endoplasmic reticulum (ER) homeostasis requires molecular regulators that tailor mitochondrial bioenergetics to the needs of protein folding. For instance, calnexin maintains mitochondria metabolism and mitochondria-ER contacts (MERCs) through reactive oxygen species (ROS) from NADPH oxidase 4 (NOX4). However, induction of ER stress requires a quick molecular rewiring of mitochondria to adapt to new energy needs. This machinery is not characterized. We now show that the oxidoreductase ERO1⍺ covalently interacts with protein kinase RNA-like ER kinase (PERK) upon treatment with tunicamycin. The PERK-ERO1⍺ interaction requires the C-terminal active site of ERO1⍺ and cysteine 216 of PERK. Moreover, we show that the PERK-ERO1⍺ complex promotes oxidization of MERC proteins and controls mitochondrial dynamics. Using proteinaceous probes, we determined that these functions improve ER-mitochondria Ca²⁺ flux to maintain bioenergetics in both organelles, while limiting oxidative stress. Therefore, the PERK-ERO1⍺ complex is a key molecular machinery that allows quick metabolic adaptation to ER stress.

100 项与 EN460 相关的药物交易

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