Modulating the phosphorylation status of target proteins through bifunctional molecules

Phosphorylation is an important form of protein post-translational modification (PTM) in cells. Dysregulation of phosphorylation is closely associated with many diseases. Because the regulation of proteins of interest (POIs) by chemically induced proximity (CIP) strategies has been widely validated, regulating the phosphorylation status of POIs by phosphorylation-regulating bifunctional molecules (PBMs) emerges as an alternative paradigm. PBMs promote the spatial proximity of POIs to kinases/phosphatases, and thus alter the phosphorylation state of POIs. Herein, we describe the history and current status of PBMs, analyze in detail the general design principles and specific applications of PBMs, assess their current advantages, possible challenges and limitations, and propose future directions for PBMs, which will stimulate interest in PBM research.