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Preventing Proteostasis Diseases by Selective Inhibition of a Phosphatase Regulatory Subunit

Preventing Proteostasis Diseases by Selective Inhibition of a Phosphatase Regulatory Subunit

Indrajit Das, Agnieszka Krzyzosiak, Kim Schneider, Lawrence Wrabetz, Maurizio D'Antonio, Nicholas Barry, Anna Sigurdardottir, Anne Bertolotti

Science. 2015 Apr 10;348(6231):239-42.

PMID: 25859045

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP951441046	Sephin1		951441-04-6	Price

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