Protein phosphorylation regulates virtually all biological processes. Although protein kinases are popular drug targets, targeting protein phosphatases has been a challenge. We have discovered small molecules that safely and selectively inhibit a regulatory subunit of protein phosphatase 1 (PP1) in cells and in vivo. One of the small-molecule inhibitors is Sephin1, which selectively binds and inhibits the stress-induced PP1 regulatory subunit PPP1R15A, but not the related and constitutive PPP1R15B. Sephin1 thereby prolongs the benefit of an adaptive phospho-signaling pathway and protects cells from otherwise lethal protein misfolding stress. In vivo, Sephin1 selectively inhibits PPP1R15A to safely prevent the motor, morphological and molecular defects of two otherwise unrelated protein misfolding diseases in mice: the neurodegenerative diseases Charcot-Marie-Tooth 1B and amyotrophic lateral sclerosis (ALS). This demonstrates that regulatory subunits of phosphatases are drug targets, a property we exploited to safely prevent two neurodegenerative diseases in mice. We now show, using multiple quantitative readouts, that Sephin1 treatment initiated after disease onset slows down the progression of the disease in an aggressive model of ALS. This demonstrates the therapeutic potential of selective phosphatase inhibition.<br/>Because there are hundreds of phosphatases that could in principle be inhibited using the same paradigm, selective inhibition of phosphatases by targeting their regulatory subunits may open up a broad range of possibilities to safely and selectively manipulate cellular functions, perhaps for therapeutic benefit.

Selective inhibition of a phosphatase to treat neurodegenerative diseases

253rd National Meeting (2017)

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