1. Academic Validation
  2. Target-Based Discovery of an Inhibitor of the Regulatory Phosphatase PPP1R15B

Target-Based Discovery of an Inhibitor of the Regulatory Phosphatase PPP1R15B

  • Cell. 2018 Aug 23;174(5):1216-1228.e19. doi: 10.1016/j.cell.2018.06.030.
Agnieszka Krzyzosiak 1 Anna Sigurdardottir 1 Laura Luh 1 Marta Carrara 1 Indrajit Das 1 Kim Schneider 1 Anne Bertolotti 2
Affiliations

Affiliations

  • 1 Neurobiology Division, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
  • 2 Neurobiology Division, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. Electronic address: aberto@mrc-lmb.cam.ac.uk.
Abstract

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.

Keywords

Huntington’s disease; PPP1R15B; drug discovery; eukaryotic initiation factor-2; neurodegenerative diseases; protein misfolding; protein phosphatase 1; protein quality control; proteostasis; stress response.

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