Modulating phosphorylation by proximity-inducing strategy: an update.

Abstract

Protein phosphorylation is dynamically controlled by kinases and phosphatases, and its dysregulation contributes to diverse disease-relevant states. Although conventional kinase modulators have enabled important therapeutic advances, direct kinase or phosphatase modulation often lacks the precision needed to correct phosphorylation at the level of a defined protein of interest (POI). Proximity-inducing modalities, particularly phosphorylation-inducing chimeric small molecules (PHICSs) and phosphatase-recruiting chimeras (PHORCs), offer an event-driven strategy to modulate phosphorylation by recruiting catalytic effectors to selected targets. Recent studies have extended PHICSs beyond early proof-of-concept systems, highlighting both improved pan-AMPK recruitment strategies and self-recruiting designs that redirect oncogenic kinase activity toward inhibitory phosphorylation. In parallel, recent PHORC studies have diversified induced dephosphorylation, spanning tag-based signaling rewiring, simultaneous PP5 recruitment and activation, and aptamer-guided PTPRF recruitment for receptor regulation. Together, these studies highlight the expanding scope of proximity-induced phosphorylation control, while emphasizing that broader application will depend on improved molecular design and a clearer understanding of proximity-driven mechanisms.