预约演示

更新于：2025-05-07

EIF2AK4 x EIF2AK1 x PERK

更新于：2025-05-07

基本信息

关联

项与 EIF2AK4 x EIF2AK1 x PERK 相关的药物

CRD-1367799

靶点

EIF2AK1 x EIF2AK4 x PERK

作用机制

EIF2AK1抑制剂 [+2]

在研机构

Graduate School of Engineering Science [+1]

原研机构

Chordia Therapeutics, Inc.

在研适应症

多发性骨髓瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

AST-0555

靶点

EIF2AK1 x EIF2AK4 x PERK

作用机制

EIF2AK1抑制剂 [+2]

在研机构

Aston SCI

原研机构

Aston SCI

在研适应症

镰状细胞血症 [+2]

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 EIF2AK4 x EIF2AK1 x PERK 相关的临床结果

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100 项与 EIF2AK4 x EIF2AK1 x PERK 相关的转化医学

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0 项与 EIF2AK4 x EIF2AK1 x PERK 相关的专利（医药）

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项与 EIF2AK4 x EIF2AK1 x PERK 相关的文献（医药）

2025-02-24·Current Neuropharmacology

ISR Modulators in Neurological Diseases

Article

作者: Parfyonova, Yelena Victorovna ; Zubkova, Ekaterina Sergeevna ; Kalinin, Alexander Pavlovich ; Menshikov, Mikhail Yuryevich

Abstract:The dysfunction of different cells lies in the pathogenesis of neurological diseases and is usually associated with cellular stress. Various stressors trigger the integrated stress response (ISR) signaling, whose highly conserved mechanism is primarily aimed at protecting a stress-exposed cell to cope as safely as possible with such stressful conditions. On the contrary, if a cell is unable to cope with excessive stress, the ISR can induce apoptosis. The ISR mechanism, whose main stage is the inhibition of translation machinery in favor of the synthesis of specific proteins, including the transcription factors ATF3, ATF4, CEBPA, and CEBPB, which function only as dimers and determine the uniqueness of the ISR response in each individual case, thus ensures different outcomes of the ISR. Inhibition of global protein synthesis is achieved through phosphorylation of eIF2α by PERK, HRI, PKR, or GCN2. To date, a number of compounds have been developed that modulate the ISR, including activators and inhibitors of the abovementioned ISR kinases as well as modulators of p-eIF2α dephosphorylation. They target different ISR stages, allowing a broad ISR modulation strategy. At the same time, there are no drugs that are both exceptionally safe and effective for the treatment of several neurological diseases, so there is an urgent need for new approaches to the treatment of these disorders. In this review, we represent ISR signaling as an important participant in the pathogenesis of neurological diseases. We also describe how various ISR modulators may become a part of future therapies for these diseases.

2024-10-07·Journal of Cell Biology

Integrated stress response activator halofuginone protects mice from diabetes-like phenotypes

Article

作者: Bertolotti, Anne ; Rai, Shashank ; Szaruga, Maria ; Pitera, Aleksandra P.

The integrated stress response (ISR) is a vital signaling pathway initiated by four kinases, PERK, GCN2, HRI and PKR, that ensure cellular resilience and protect cells from challenges. Here, we investigated whether increasing ISR signaling could rescue diabetes-like phenotypes in a mouse model of diet-induced obesity (DIO). We show that the orally available and clinically approved GCN2 activator halofuginone (HF) can activate the ISR in mouse tissues. We found that daily oral administration of HF increases glucose tolerance whilst reducing weight gain, insulin resistance, and serum insulin in DIO mice. Conversely, the ISR inhibitor GSK2656157, used at low doses to optimize its selectivity, aggravates glucose intolerance in DIO mice. Whilst loss of function mutations in mice and humans have revealed that PERK is the essential ISR kinase that protects from diabetes, our work demonstrates the therapeutic value of increasing ISR signaling by activating the related kinase GCN2 to reduce diabetes phenotypes in a DIO mouse model.

2024-07-01·Journal of Molecular Biology

GCN2 in Viral Defence and the Subversive Tactics Employed by Viruses

Review

作者: Sattlegger, Evelyn ; Sansom, Bianca J M ; Gibbs, Victoria J ; Lin, Yu H ; Conaglen, Layla ; Schiemann, Anja H ; Ghuge, Aditi A ; Anderson, Reuben A ; da Silva, Richard C

The recent SARS-CoV-2 pandemic and associated COVID19 disease illustrates the important role of viral defence mechanisms in ensuring survival and recovery of the host or patient. Viruses absolutely depend on the host's protein synthesis machinery to replicate, meaning that impeding translation is a powerful way to counteract viruses. One major approach used by cells to obstruct protein synthesis is to phosphorylate the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α). Mammals possess four different eIF2α-kinases: PKR, HRI, PEK/PERK, and GCN2. While PKR is currently considered the principal eIF2α-kinase involved in viral defence, the other eIF2α-kinases have also been found to play significant roles. Unsurprisingly, viruses have developed mechanisms to counteract the actions of eIF2α-kinases, or even to exploit them to their benefit. While some of these virulence factors are specific to one eIF2α-kinase, such as GCN2, others target all eIF2α-kinases. This review critically evaluates the current knowledge of viral mechanisms targeting the eIF2α-kinase GCN2. A detailed and in-depth understanding of the molecular mechanisms by which viruses evade host defence mechanisms will help to inform the development of powerful anti-viral measures.

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