Targeting phosphatases: From molecule design to clinical trials

Area of Science:

• Biochemistry
• Enzymology
• Pharmacology

Background:

• Phosphatases dephosphorylate proteins and are implicated in various diseases, notably cancers.
• Despite their disease relevance, phosphatases have been historically considered
• undruggable" targets due to challenges in small molecule inhibitor development.

Purpose of the Study:

• To review recent strategies for designing small molecule inhibitors targeting phosphatases.
• To highlight the progress and potential of phosphatases as therapeutic targets.

Main Methods:

• Classification of phosphatase inhibitors into four categories: molecular glues, catalytic site inhibitors, allosteric inhibitors, and bifunctional molecules (PROTACs).
• Review of emerging therapeutic strategies and clinical trial advancements.

Main Results:

• Diverse small molecule inhibitor strategies, including PROTACs, are progressing into clinical trials.
• Combination therapies involving phosphatase inhibitors are also under clinical investigation.

Conclusions:

• The development of novel small molecule inhibitors demonstrates the feasibility of targeting phosphatases.
• Targeting phosphatases represents a promising therapeutic avenue for modulating pathogenetic phosphorylation and treating diseases.