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Details

Stereochemistry ACHIRAL
Molecular Formula C8H9ClN4.C2H4O2
Molecular Weight 256.689
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 1
Charge 0

SHOW SMILES / InChI
Structure of ICERGUASTAT ACETATE

SMILES

CC(O)=O.NC(=N)N\N=C\C1=CC=CC=C1Cl

InChI

InChIKey=WEXITTWZMLUGNU-NKPNRJPBSA-N
InChI=1S/C8H9ClN4.C2H4O2/c9-7-4-2-1-3-6(7)5-12-13-8(10)11;1-2(3)4/h1-5H,(H4,10,11,13);1H3,(H,3,4)/b12-5+;

HIDE SMILES / InChI

Description

Sephin1 is a guanabenz derivative that binds to and inhibits a regulatory subunit of the stress-induced protein phosphatase 1 (PPP1R15A), but not the constitutive PPP1R15B, and lacks beta2-adrenergic activity. Phosphorylation of eIF2α, α subunit of eukaryotic translation initiation factor 2, reduces protein synthesis and prevents the accumulation of misfolded protein in the endoplasmic reticulum (ER). PPP1R15A recruits the serine/threonine-protein phosphatase PP1 to dephosphorylate eIF2α, so inhibiting PPP1R15A activity prolongs the phosphorylation of eIF2α and aids in its prevention of the accumulation of misfolded protein. In vitro, Sephin1 protected cells from lethal protein misfolding and cytotoxic ER stress. In vivo Sephin1 prevented Charcot-Marie-Tooth 1B and ALS diseases in mice.

Originator

Approval Year

Targets

Primary TargetPharmacologyConditionPotency

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown
Primary
Unknown
Primary
Unknown

PubMed

Patents

Sample Use Guides

In Vivo Use Guide
Mice were treated orally with Sephin1 (1 mg/kg) or vehicle twice a day, from postnatal days 28 to 61.
Route of Administration: Oral
In Vitro Use Guide
Cells were plated in 24-well plates at a density of 15,000 (HeLa) or 12,000 cells/ml (MEFs) 24 hours prior to treatment. ER stress was elicited by addition of fresh media containing 2.5 µg/ml tunicamycin (Sigma-Aldrich). Sephin1 were dissolved in DMSO and added at 50mkM. Cell viability was assessed by measuring the reduction of WST-8 [2-(2-methoxy-4-nitrophenyl)-3-(4- nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium] into formazan using Cell viability Counting Kit-8 (Dojindo) according to the supplier’s recommendation, 48 hours after tunicamycin treatment.