Deciphering phosphorylation TACtics: Advances in phosphorylation targeting strategies and bifunctional modalities

Phosphorylation dynamics are delicately balanced by kinases and phosphatases, and abnormal protein phosphorylation events may disrupt normal cellular physiology and thus lead to diseases. Recent developments in phosphorylation targeting tools-mostly the small-molecule kinase inhibitors-have changed the treatments for cancers and other diseases. Alternatively, the use of bifunctional modalities offers another approach through an "event-driven model" with distinct advantages. Here, we highlight advances in bifunctional modalities that modulate protein phosphorylation, including PhosTACs, DEPTACs, PhoRCs, PHICS, and related approaches. Starting with an overview of both kinases and phosphates, we describe recent applications of phosphorylation-targeting therapeutics, with a discussion about the advantages and limitations of current tools, and alternative solutions using bifunctional systems. In addition, the modes of action of various bifunctional modalities and the interplay among protein substrates, kinases, and phosphatases are also discussed, offering an insight into the advancements of phosphorylation targeting strategies against human diseases.