Modulating phosphorylation by proximity-inducing strategy: an update

Area of Science:

• Biochemistry
• Molecular Biology
• Chemical Biology

Background:

• Protein phosphorylation is a critical cellular process regulated by kinases and phosphatases.
• Dysregulation of phosphorylation is implicated in various diseases.
• Current kinase/phosphatase modulators lack precision for targeting specific proteins.

Purpose of the Study:

• To review recent advancements in proximity-inducing modalities for precise phosphorylation control.
• To highlight the development and application of phosphorylation-inducing chimeric small molecules (PHICSs) and phosphatase-recruiting chimeras (PHORCs).
• To discuss the potential and challenges for broader application of these targeted approaches.

Main Methods:

• Development of novel chimeric small molecules (PHICSs) for targeted kinase recruitment and modulation.
• Design of phosphatase-recruiting chimeras (PHORCs) for induced dephosphorylation.
• Exploration of strategies including pan-AMPK recruitment, self-recruiting designs, tag-based signaling rewiring, and aptamer-guided recruitment.

Main Results:

• PHICSs have been advanced beyond proof-of-concept, with improved recruitment strategies and designs redirecting oncogenic kinase activity.
• PHORCs have demonstrated diverse applications in induced dephosphorylation, including PP5 activation and PTPRF recruitment.
• These studies showcase the expanding capabilities of proximity-induced phosphorylation control.

Conclusions:

• Proximity-inducing modalities offer a precise, event-driven strategy to modulate protein phosphorylation.
• Further improvements in molecular design and mechanistic understanding are crucial for broader clinical application.
• These targeted approaches hold significant promise for treating diseases linked to phosphorylation dysregulation.