1597403-47-8 Usage
Description
ISRIB (trans-isomer), the trans-isomer of ISRIB, is a potent and selective PERK inhibitor with an IC50 of 5 nM. It does not have global effects on translation, transcription, or mRNA stability in non-stressed cells. ISRIB (trans-isoMer) acts as an integrated stress response (ISR) inhibitor, reversing the effects of eIF2α phosphorylation and restoring cell translation capacity. It acts downstream of PERK, targeting interactions between eIF2α kinases and eIF2B, and blocks ATF4 production without altering the IRE1 or ATF6 responses in vitro. Additionally, trans-ISRIB displays memory enhancement in hippocampus-dependent spatial and fear-associated learning in rodents and promotes the survival of pluripotent stem cells in culture when used in combination with Chroman-1, emricasan, and polyamines, a combination known as CEPT.
Uses
Used in Pharmaceutical Applications:
ISRIB (trans-isomer) is used as an integrated stress response inhibitor for its ability to reverse the effects of eIF2α phosphorylation, restore cell translation capacity, and block ATF4 production without affecting IRE1 or ATF6 responses. This makes it a promising candidate for the development of therapeutic strategies targeting various diseases and conditions associated with the integrated stress response.
Used in Neurological Applications:
ISRIB (trans-isomer) is used as a memory enhancer for its ability to improve hippocampus-dependent spatial and fear-associated learning in rodents. This suggests potential applications in the treatment of neurological disorders and conditions related to cognitive impairment or memory loss.
Used in Stem Cell Research:
ISRIB (trans-isomer) is used as a survival promoter for pluripotent stem cells in culture when used in combination with Chroman-1, emricasan, and polyamines (CEPT cocktail). This application highlights its potential in advancing stem cell research and therapies, particularly in the context of regenerative medicine and tissue engineering.
Used in Cryopreservation:
ISRIB (trans-isomer) is used as a survival improver for differentiated cells following cryopreservation when used as part of the CEPT cocktail. This application suggests its potential in enhancing the viability and functionality of cryopreserved cells, which could be beneficial for various medical and research applications, including cell banking and transplantation.
Biological Functions
ISRIB (trans-isomer) is a potent inhibitor of the integrated stress response (ISR).Integrated stress response (ISR) is activated by diverse cellular conditions and rapidly reduces overall protein synthesis while enhancing translation of specific transcripts that support adaptive stress responses. The ISR is mediated by diverse stress-sensing kinases that phosphorylating serine 51 in eukaryotic translation initiation factor alpha (eIF2α).ISRIB (trans-isomer) is a potent ISR inhibitor. ISRIB reversed the effects of eIF2α phosphorylation with IC50 value of 5 nM. ISRIB inhibited production of endogenous ATF4 (a cAMP element binding transcription factor). In mouse embryonic fibroblasts (MEFs), ISRIB reversed the increase in the 80S monosomes at the expense of polyribosomes induced by endoplasmic reticulum (ER) stress. In ER-stressed cells, ISRIB reduced cell survival. In stressed cells, ISRIB restored mRNA translation and inhibited stress granule (SG) formation induced by eIF2α phosphorylation. ISRIB inhibited the interaction between eIF2B and eIF2 that located at the core of the ISR. Also, ISRIB was an activator of eIF2B and stabilized activated eIF2B dimers.In mice, ISRIB significantly increased hippocampus-dependent spatial and fear-associated learning.
Biological Activity
ISRIB (integrated stress response inhibitor) as a drug, imparts resistance to the cells against the downstream effects of eukaryotic initiation factor 2 (eIF2)α phosphorylation such as activating transcription factor 4 (ATF4) and eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) induction.ISRIB is a blood- brain barrier penetrant, potent and selective inhibitor of integrated stress response (ISR) that impairs adaptation to ER stress. ISRIB is a potent inhibitor of PERK signaling, which potently reverses the effects of eIF2a phosphorylation and restores the cells translation capacity. ISRIB enhances cognitive memory in rodents.
Biochem/physiol Actions
ISRIB (integrated stress response inhibitor) as a drug, imparts resistance to the cells against the downstream effects of eukaryotic initiation factor 2 (eIF2)α phosphorylation such as activating transcription factor 4 (ATF4) and eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) induction.
References
[1]. Sidrauski C, Acosta-Alvear D, Khoutorsky A, et al. Pharmacological brake-release of mRNA translation enhances cognitive memory. Elife, 2013, 2: e00498.[2]. Sidrauski C, McGeachy AM, Ingolia NT, et al. The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly. Elife, 2015, 4.[3]. Sekine Y, Zyryanova A, Crespillo-Casado A, et al. Stress responses. Mutations in a translation initiation factor identify the target of a memory-enhancing compound. Science, 2015, 348(6238): 1027-1030.[4]. Sidrauski C, Tsai JC, Kampmann M, et al. Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response. Elife, 2015, 4: e07314.
Check Digit Verification of cas no
The CAS Registry Mumber 1597403-47-8 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,5,9,7,4,0 and 3 respectively; the second part has 2 digits, 4 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 1597403-47:
(9*1)+(8*5)+(7*9)+(6*7)+(5*4)+(4*0)+(3*3)+(2*4)+(1*7)=198
198 % 10 = 8
So 1597403-47-8 is a valid CAS Registry Number.
1597403-47-8Relevant articles and documents
MODULATORS OF THE EIF2ALPHA PATHWAY
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Paragraph 0410, (2014/09/29)
Provided herein, inter alia, are compounds and methods useful for modulating the translational effects of eIF2 phosphorylation, the Integrated Stress Response (ISR), and the unfolded protein response (UPR); for treating diseases; for increasing protein production, and for improving long-term memory.