Raphin1

Raphin1 is an orally bioavailable, selective inhibitor of the regulatory phosphatase PPP1R15B (R15B). Raphin1 binds strongly to the R15B-PP1c holophosphatase (K_d=33 nM), and shows ~30-fold selective in binding R15B-PP1c over R15A-PP1c. Raphin1 crosses the blood-brain barrier, and reduces organismal and molecular deficits in a mouse model of a protein misfolding disease^[1]. IC50 & Target: Kd：33 nM (R15B-PP1c holophosphatase)^[1] In Vitro: Raphin1 causes a rapid and transient accumulation of its phosphorylated substrate, resulting in a transient attenuation of protein synthesis^[1].
Raphin1 inhibits the recombinant R15B-PP1c holoenzyme, but not the closely related R15A-PP1c, by interfering with substrate recruitment^[1]. In Vivo: Raphin1 improves weight of HD^82Q mice treated from 4 to ∼10 weeks of age with 2 mg/kg of Raphin1 once a day by oral gavage. Raphin1 also decreases SDS-insoluble huntingtin assemblies and nuclear inclusions in the cortex of HD^82Q mice^[1].