| First Author | Krzyzosiak A | Year | 2018 |
| Journal | Cell | Volume | 174 |
| Issue | 5 | Pages | 1216-1228.e19 |
| PubMed ID | 30057111 | Mgi Jnum | J:264858 |
| Mgi Id | MGI:6198961 | Doi | 10.1016/j.cell.2018.06.030 |
| Citation | Krzyzosiak A, et al. (2018) Target-Based Discovery of an Inhibitor of the Regulatory Phosphatase PPP1R15B. Cell 174(5):1216-1228.e19 |
| abstractText | Protein phosphorylation is a prevalent and ubiquitous mechanism of regulation. Kinases are popular drug targets, but identifying selective phosphatase inhibitors has been challenging. Here, we used surface plasmon resonance to design a method to enable target-based discovery of selective serine/threonine phosphatase inhibitors. The method targeted a regulatory subunit of protein phosphatase 1, PPP1R15B (R15B), a negative regulator of proteostasis. This yielded Raphin1, a selective inhibitor of R15B. In cells, Raphin1 caused a rapid and transient accumulation of its phosphorylated substrate, resulting in a transient attenuation of protein synthesis. In vitro, Raphin1 inhibits the recombinant R15B-PP1c holoenzyme, but not the closely related R15A-PP1c, by interfering with substrate recruitment. Raphin1 was orally bioavailable, crossed the blood-brain barrier, and demonstrated efficacy in a mouse model of Huntington's disease. This identifies R15B as a druggable target and provides a platform for target-based discovery of inhibitors of serine/threonine phosphatases. |
