Last update 01 Nov 2024

EIF2AK1 x PERK x EIF2AK4

Last update 01 Nov 2024

Basic Info

Related Targets

EIF2AK1PERKEIF2AK4

Drugs associated with EIF2AK1 x PERK x EIF2AK4

CRD-1367799

Target

EIF2AK1 x EIF2AK4 x PERK

Mechanism

EIF2AK1 inhibitors [+2]

Active Org.

Chordia Therapeutics, Inc.Startup

Originator Org.

Chordia Therapeutics, Inc.Startup

Active Indication

Multiple Myeloma

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with EIF2AK1 x PERK x EIF2AK4

100 Translational Medicine associated with EIF2AK1 x PERK x EIF2AK4

0 Patents (Medical) associated with EIF2AK1 x PERK x EIF2AK4

Literatures (Medical) associated with EIF2AK1 x PERK x EIF2AK4

07 Oct 2024·Journal of Cell Biology

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

Article

Author: 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.

01 Jul 2024·Journal of Molecular Biology

GCN2 in Viral Defence and the Subversive Tactics Employed by Viruses

Review

Author: 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.

01 Jun 2024·Acta Pharmacologica Sinica

Mammalian integrated stress responses in stressed organelles and their functions

Review

Author: Lu, Hao-Jun ; Sheng, Rui ; Koju, Nirmala

The integrated stress response (ISR) triggered in response to various cellular stress enables mammalian cells to effectively cope with diverse stressful conditions while maintaining their normal functions. Four kinases (PERK, PKR, GCN2, and HRI) of ISR regulate ISR signaling and intracellular protein translation via mediating the phosphorylation of eukaryotic translation initiation factor 2 α (eIF2α) at Ser51. Early ISR creates an opportunity for cells to repair themselves and restore homeostasis. This effect, however, is reversed in the late stages of ISR. Currently, some studies have shown the non-negligible impact of ISR on diseases such as ischemic diseases, cognitive impairment, metabolic syndrome, cancer, vanishing white matter, etc. Hence, artificial regulation of ISR and its signaling with ISR modulators becomes a promising therapeutic strategy for relieving disease symptoms and improving clinical outcomes. Here, we provide an overview of the essential mechanisms of ISR and describe the ISR-related pathways in organelles including mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes. Meanwhile, the regulatory effects of ISR modulators and their potential application in various diseases are also enumerated.

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