Salubrinal

IC50: A cell-permeable and selective inhibitor of eIF2α dephosphorylation with an IC50 of 15 M.

The eukaryotic translation initiation factor 2 subunit α (eIF2α) is crucial in protein synthesis. eIF2α phosphorylation played an important role in protecting cells from apoptosis. Salubrinal selectively suppresses the phosphatase complexes that dephosphorylate eIF-2α. [1]

In vitro: This agent is reported to protect cells from endoplasmic reticulum (ER) stress-induced apoptosis (EC50 ~15 M) in PC12 cell lines induced with the protein glycosylation inhibitor tunicamycin and brefeldin A, which causes ER stress by blocking ER-to-Golgi vesicle transport. Salubrinal is a potentially useful agent to study mechanisms of ER stress-induced apoptosis. In addition, it was reported that salubrinal at 50 μM prevented cells from the autophagic and apoptotic progresses induced by loss of Bcl-2 function in murine leukemia L1210 cells. [1]

In vivo: Study from male ICR mice showed that salubrinal significantly aggravated the cisplatin-induced nephrotoxicity. In the kidneys of cisplatin-treated mice, the phosphorylation of eIF2α was significantly increased by salubrinal. In addition, the expression of CCAAT/enhancer binding protein, activating transcription factor 4 as well as the cleavage of caspases 3, 9 and 12 were also up-regulated. Moreover, salubrinal also increased the cisplatin-induced oxidative stress. These findings indicated that salubrinal aggravated cisplatin-induced nephrotoxicity via the up-regulation of ER stress-related cell apoptosis and oxidative stress. [2]

Clinical trial: So far, no clinical trial has been conducted.

References:
[1] Kessel D.  Protection of Bcl-2 by salubrinal. Biochem Bioph Res Co. 2006; 346: 1320-3.
[2] Wu CT, Sheu ML, Tsai KS, Chiang CK and Liu SH.  Salubrinal, an eIF2α dephosphorylation inhibitor, enhances cisplatin-induced oxidative stress and nephrotoxicity in a mouse model. Free Radic Biol Med, 2011; 51(3): 671-680.

Salubrinal Alleviates Pressure Overload-Induced Cardiac Hypertrophy by Inhibiting Endoplasmic Reticulum Stress Pathway.[Pubmed:28152298]

Mol Cells. 2017 Jan;40(1):66-72.

Pathological hypertrophy of the heart is closely associated with endoplasmic reticulum stress (ERS), leading to maladaptations such as myocardial fibrosis, induction of apoptosis, and cardiac dysfunctions. Salubrinal is a known selective inhibitor of protein phosphatase 1 (PP1) complex involving dephosphorylation of phospho-eukaryotic translation initiation factor 2 subunit (p-eIF2)-alpha, the key signaling process in the ERS pathway. In this study, the effects of Salubrinal were examined on cardiac hypertrophy using the mouse model of transverse aortic constriction (TAC) and cell model of neonatal rat ventricular myocytes (NRVMs). Treatment of TAC-induced mice with Salubrinal (0.5 mg.kg(-1).day(-1)) alleviated cardiac hypertrophy and tissue fibrosis. Salubrinal also alleviated hypertrophic growth in endothelin 1 (ET1)-treated NRVMs. Therefore, the present results suggest that Salubrinal may be a potentially efficacious drug for treating pathological cardiac remodeling.

Synergistic antitumor activity of the combination of salubrinal and rapamycin against human cholangiocarcinoma cells.[Pubmed:27863431]

Oncotarget. 2016 Dec 20;7(51):85492-85501.

Less is known about the roles of eukaryotic initiation factor alpha (eIF2alpha) in cholangiocarcinoma (CCA). Here, we report that eIF2alpha inhibitor Salubrinal inhibits the proliferation of human CCA cells. Clinical application of mammalian target of rapamycin (mTOR) inhibitors only has moderate antitumor efficacy. Therefore, combination approaches may be required for effective clinical use of mTOR inhibitors. Here, we investigated the efficacy of the combination of Salubrinal and rapamycin in the treatment of CCA. Our data demonstrate a synergistic antitumor effect of the combination of Salubrinal and rapamycin against CCA cells. Rapamycin significantly inhibits the proliferation of CCA cells. However, rapamycin initiates a negative feedback activation of Akt. Inhibition of Akt by Salubrinal potentiates the efficacy of rapamycin both in vitro and in vivo. Additionally, rapamycin treatment results in the up-regulation of Bcl-xL in a xenograft mouse model. It is notable that Salubrinal inhibits rapamycin-induced Bcl-xL up-regulation in vivo. Taken together, our data suggest that Salubrinal and rapamycin combination might be a new and effective strategy for the treatment of CCA.

Salubrinal protects against Clostridium difficile toxin B-induced CT26 cell death.[Pubmed:28119311]

Acta Biochim Biophys Sin (Shanghai). 2017 Mar 1;49(3):228-237.

Clostridium difficile (C. difficile) is considered to be the major cause of the antibiotic-associated diarrhea and pseudomembranous colitis in animals and humans. The prevalence of C. difficile infections (CDI) has been increasing since 2000. Two exotoxins of C. difficile, Toxin A (TcdA) and Toxin B (TcdB), are the main virulence factors of CDI, which can induce glucosylation of Rho GTPases in host cytosol, leading to cell morphological changes, cell apoptosis, and cell death. The mechanism of TcdB-induced cell death has been investigated for decades, but it is still not completely understood. It has been reported that TcdB induces endoplasmic reticulum stress via PERK-eIF2alpha signaling pathway in CT26 cell line (BALB/C mouse colon tumor cells). In this study, we found that Salubrinal, a selective inhibitor of eIF2alpha dephosphorylation, efficiently protects CT26 cell line against TcdB-induced cell death and tried to explore the mechanism underlying in this protective effect. Our results demonstrated that Salubrinal protects CT26 cells from TcdB-mediated cytotoxic and cytopathic effect, inhibits apoptosis and death of the toxin-exposed cells via caspase-9-dependent pathway, eIF2alpha signaling pathway, and autophagy. These findings will be helpful for the development of CDI therapies.

A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress.[Pubmed:15705855]

Science. 2005 Feb 11;307(5711):935-9.

Most protein phosphatases have little intrinsic substrate specificity, making selective pharmacological inhibition of specific dephosphorylation reactions a challenging problem. In a screen for small molecules that protect cells from endoplasmic reticulum (ER) stress, we identified Salubrinal, a selective inhibitor of cellular complexes that dephosphorylate eukaryotic translation initiation factor 2 subunit alpha (eIF2alpha). Salubrinal also blocks eIF2alpha dephosphorylation mediated by a herpes simplex virus protein and inhibits viral replication. These results suggest that selective chemical inhibitors of eIF2alpha dephosphorylation may be useful in diseases involving ER stress or viral infection. More broadly, Salubrinal demonstrates the feasibility of selective pharmacological targeting of cellular dephosphorylation events.

Structure-activity relationship studies of salubrinal lead to its active biotinylated derivative.[Pubmed:16002288]

Bioorg Med Chem Lett. 2005 Sep 1;15(17):3849-52.

The synthesis and structure-activity relationships (SAR) of Salubrinal, a small molecule that protects cells from apoptosis induced by endoplasmic reticulum (ER) stress, are described. It is revealed that the trichloromethyl group greatly contributes to the activity. Based on the SAR results, Salubrinal was converted into a biotinylated derivative which retains activity and can be used as a biological tool for target identification.

Salubrinal is a selective inhibitor of eIF2α dephosphorylation and inhibits ER stress-mediated apoptosis with EC50 of ~15 μM in a cell-free assay.

Salubrinal,405060-95-9,Natural Products,eIF2a, buy Salubrinal , Salubrinal supplier , purchase Salubrinal , Salubrinal cost , Salubrinal manufacturer , order Salubrinal , high purity Salubrinal