| First Author | Das I | Year | 2015 |
| Journal | Science | Volume | 348 |
| Issue | 6231 | Pages | 239-42 |
| PubMed ID | 25859045 | Mgi Jnum | J:221856 |
| Mgi Id | MGI:5641768 | Doi | 10.1126/science.aaa4484 |
| Citation | Das I, et al. (2015) Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit. Science 348(6231):239-42 |
| abstractText | 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. |
