イスリブ 化学特性,用途語,生産方法
説明
ISRIB (integrated stress response inhibitor) is an experimental drug that reverses the effects of eIF2α phosphorylation with an IC50 of 5 nM. It was discovered in the laboratory of Peter Walter at University of California, San Francisco (UCSF) through a semi-automated screening of a large library of small molecules by Carmela Sidrauski, who decided to pursue research on it. It has been shown to inhibit eIF2α phosphorylation-induced stress granule (SG) formation. Since eIF2α phosphorylation is known to be involved in memory formation, ISRIB was tested to see whether it would be active in vivo, and was found to readily cross the blood-brain barrier, with a half-life of eight hours.
使用
ISRIB (mix-Isomer), is a symmetric bis-glycolamide that inhibits integrated stress response (ISR). In wild-type mice studies has shown that it improved memory by efficiently reversing the effects of eIF2α phosphorylation, which has brought expectation that inhibition of PERK signaling may have the potential to ameliorate Alzheimer's disease. In a present study ISRIB demonstrated to attenuate amyloid b-induced neuronal cell death although the pharmacological mechanisms of this action have not yet been elucidated.
主な応用
ISRIB (integrated stress response inhibitor) has been used as an inhibitor of integrated stress response.
生物活性
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.
安全性
The safety of ISRIB in humans is currently unknown, though there may be toxicity in certain animal models.
Types of evidence:
Multiple preclinical studies
In an Alzheimer's animal model, a dose of ISRIB too high (5mg/kg) caused excessive mortality and the dose had to be lowered (Briggs et al, 2017). An effective, yet non-lethal dose and dosing schedule, has yet to be determined and may depend on the particular disease being treated. Whether long-term treatment with ISRIB is safe is also not yet determined.
薬物相互作用
Drug interactions have not been studies; though ISRIB could potentially interact with drugs that have been reported to act on the integrated stress response pathway (e.g., trazodone, Halliday et al, 2017).
イスリブ 上流と下流の製品情報
原材料
準備製品