Targeting the untargetable: recent advances in the selective chemical modulation of protein phosphatase-1 activity

• Protein phosphatase-1 (PP1) is an important enzyme in health and disease.
• Chemical compounds that are available to perturb PP1 signaling are reviewed.
• Therapeutic relevance of the chemical tools is discussed.
• Remaining challenges and novel approaches to them are considered.

Protein phosphatase-1 (PP1) has long been neglected as a potential drug target owing to its misinterpreted unselective nature. However, growing evidence demonstrates that PP1 is highly selective in complex with regulatory proteins at the holoenzyme level, each of which is involved in different essential cellular signaling events. Here we summarize promising approaches to specifically activate or inhibit PP1 activity, and discuss remaining challenges and potential solutions. The summarized chemical tools pave the way for a better understanding of PP1's role in signaling networks, and the effects resulting from their application suggest their potential as future therapeutic candidates.