(E)-2-(2-Chlorobenzylidene)hydrazinecarboximidamide; 2-[(2-Chlorophenyl)methylene]hydrazinecarboximidamide

Sephin 1 is a selective inhibitor of holophosphatase, a regulatory subunit of protein phosphatase 1

Chemical Formula: C8H9ClN4

Molecular Weight: 196.6

OTAVAchemicals Catalogue Number: 0114360035

CAS Registry Number: 13098-73-2

Purity: 95%+ (HPLC)

Ref.: Das, I. et al.: Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit. Science. 2015;348:239–242

Abstract: Protein phosphorylation regulates virtually all biological processes. Although protein kinases are popular drug targets, targeting protein phosphatases remains a challenge. Here, we describe Sephin1 (selective inhibitor of a holophosphatase), a small molecule that safely and selectively inhibited a regulatory subunit of protein phosphatase 1 in vivo. Sephin1 selectively bound and inhibited the stress-induced PPP1R15A, but not the related and constitutive PPP1R15B, to prolong the benefit of an adaptive phospho-signaling pathway, protecting cells from otherwise lethal protein misfolding stress. In vivo, Sephin1 safely prevented the motor, morphological, and molecular defects of two otherwise unrelated protein-misfolding diseases in mice, Charcot-Marie-Tooth 1B, and amyotrophic lateral sclerosis. Thus, regulatory subunits of phosphatases are drug targets, a property exploited here to safely prevent two protein misfolding diseases. May be used in the prevention of protein misfolding diseases.

DOI: 10.1126/science.aaa4484