ISRIB
IC50: 5 nM
ISRIB is a potent inhibitor of PERK signaling.
As one of the four eIF2α kinases in mammalian cells, PERK responds to an accumulation of unfolded proteins in the endoplasmic reticulum.
In vitro: Compared with cis-ISRIB, trans-ISRIB proved 100-fold more potent (IC50 = 5 nM vs IC50 = 600 nM), suggesting that ISRIB interacted with its cellular target stereospecifically. In addition, ISRIB could block the production of endogenous ATF4, while had no obvious effect on XBP1 mRNA splicing and XBP1s production. Meanwhile, ISRIB did not affect activation of the ATF6-branch of the UPR, however, ISRIB could block the downstream of PERK and eIF2α phosphorylation [1].
In vivo: In mouse with a single intraperitoneal injection, ISRIB showed a plasma half-life of 8 hr and readily crossed the blood-brain barrier with quick equilibrium in the central nervous system. The detected brain ISRIB concentrations were found to be several fold higher than its IC50. Moreover, ISRIB-treated mice displayed significant enhancement in spatial and fear-associated learning. Therefore, memory consolidation was inherently limited by the ISR, and ISRIB could release suchbrake. These results showed that ISRIB might contribute to the understanding and treatment of cognitive disorders [1].
Clinical trial: Up to now, ISRIB is still in the preclinical development stage.
Reference:
[1] Sidrauski C, et al. Pharmacological brake-release of mRNA translation enhances cognitive memory. Elife. 2013 May 28;2:e00498.
| Physical Appearance | A solid |
| Storage | Store at -20°C |
| M.Wt | 451.34 |
| Cas No. | 548470-11-7 |
| Formula | C22H24Cl2N2O4 |
| Solubility | insoluble in H2O; insoluble in EtOH; ≥15.03 mg/mL in DMSO with gentle warming |
| Chemical Name | (1Z,1'Z)-N',N''-((1r,4r)-cyclohexane-1,4-diyl)bis(2-(4-chlorophenoxy)acetimidic acid) |
| SDF | Download SDF |
| Canonical SMILES | ClC1=CC=C(OC/C(O)=N/[C@@]2([H])CC[C@@](/N=C(O)/COC3=CC=C(Cl)C=C3)([H])CC2)C=C1 |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Cell experiment:[1] | |
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Cell lines |
HEK293T cells |
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Reaction Conditions |
200 nM ISRIB for 24 h incubation |
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Applications |
Addition of ISRIB alone did not affect cell viability, but caused a strong synergistic effect on ER-stressed cells, reducing colony number and size significantly more than ER-stress alone. This reduction in cell survival resulted from activation of apoptosis as the activity of the executioner caspases 3 and/or 7 was significantly induced under these conditions. Thus, ISRIB could synergize with ER stress to induce apoptosis. |
| Animal experiment:[1] | |
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Animal models |
Eight to ten-week-old male C57BL/6J mice |
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Dosage form |
0.25 mg/kg Injected intraperitoneally |
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Applications |
In a Morris water maze, ISRIB-treated mice reached the hidden platform significantly faster compared to vehicle treated controls. The difference was already pronounced by days 3 and 4. |
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Note |
The technical data provided above is for reference only. |
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References: 1. Sidrauski C, Acosta-Alvear D, Khoutorsky A, et al. Pharmacological brake-release of mRNA translation enhances cognitive memory. Elife, 2013, 2: e00498. |
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