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

• AgnieszkA Krzyzosiak ^[1] ; Anna Sigurdardottir ^[1] ; Laura Luh ^[1]
  1. [1] MRC Laboratory of Molecular Biology

     MRC Laboratory of Molecular Biology

     Cambridge District, Reino Unido

     
• Localización: Cell, ISSN 0092-8674, Vol. 174, Nº. 5, 2018, págs. 1216-1228
• Idioma: inglés
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• Resumen

  • 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.