Sephin1

• CAT Number: I009438
• CAS Number: 951441-04-6
• Molecular Formula: C8H9ClN4
• Molecular Weight: 196.638
• Purity: ≥95%
• Synonyms: Sephin1; Sephin-1; Sephin 1.;(E)-2-(2-Chlorobenzylidene)hydrazinecarboximidamide
• Target: Phosphatase
• Solubility: Soluble in DMSO
• Storage: 0 - 4 °C for short term, or -20 °C for long term
• IUPAC Name: 2-[(E)-(2-chlorophenyl)methylideneamino]guanidine
• InChI: InChI=1S/C8H9ClN4/c9-7-4-2-1-3-6(7)5-12-13-8(10)11/h1-5H,(H4,10,11,13)/b12-5+
• InChIKey: PDWJALXSRRSUHR-LFYBBSHMSA-N
• SMILES: C1=CC=C(C(=C1)C=NN=C(N)N)Cl

Sephin1 (CAT: I009438) is a selective inhibitor of the integrated stress response (ISR), a cellular stress response pathway involved in regulating protein synthesis and cell survival under stressful conditions. By targeting the eukaryotic translation initiation factor 2-alpha kinase 1 (EIF2AK1), Sephin1 prevents the phosphorylation of EIF2α, a key step in initiating the ISR. This inhibition leads to the suppression of downstream stress response pathways and the reduction of stress-induced apoptosis. Sephin1 has shown potential in protecting against neuronal cell death in various neurodegenerative disease models and may have therapeutic implications for the treatment of such conditions.

Reference

1:Elife. 2017 Apr 27;6. pii: e26109. doi: 10.7554/eLife.26109. PPP1R15A-mediated dephosphorylation of eIF2α is unaffected by Sephin1 or Guanabenz.Crespillo-Casado A,Chambers JE,Fischer PM,Marciniak SJ,Ron D, PMID: 28447936 PMCID: PMC5429092 DOI: 10.7554/eLife.26109
Abstract: Dephosphorylation of translation initiation factor 2 (eIF2α) terminates signalling in the mammalian integrated stress response (ISR) and has emerged as a promising target for modifying the course of protein misfolding diseases. The [(o-chlorobenzylidene)amino]guanidines (Guanabenz and Sephin1) have been proposed to exert protective effects against misfolding by interfering with eIF2α-P dephosphorylation through selective disruption of a PP1-PPP1R15A holophosphatase complex. Surprisingly, they proved inert in vitro affecting neither stability of the PP1-PPP1R15A complex nor substrate-specific dephosphorylation. Furthermore, eIF2α-P dephosphorylation, assessed by a kinase shut-off experiment, progressed normally in Sephin1-treated cells. Consistent with its role in defending proteostasis, Sephin1 attenuated the IRE1 branch of the endoplasmic reticulum unfolded protein response. However, repression was noted in both wildtype and Ppp1r15a deleted cells and in cells rendered ISR-deficient by CRISPR editing of the Eif2s1 locus to encode a non-phosphorylatable eIF2α (eIF2αS51A). These findings challenge the view that [(o-chlorobenzylidene)amino]guanidines restore proteostasis by interfering with eIF2α-P dephosphorylation.