BeyondTACs: Chemical Editing of Posttranslational Modifications (PTMs) for Therapeutic Intervention.

Abstract

Protein posttranslational modifications (PTMs) build up the diversity and complexity of the proteome, and their dysregulation is intrinsically linked to various diseases. The study of PTMs has profoundly broadened the scope of therapeutic target discovery. Building upon the success of PROTACs, this heterobifunctional paradigm has expanded beyond ubiquitination to recruit diverse endogenous enzymes for proximity-induced PTM modulation (e.g., PHICS, AceTACs, and DUBTACs). As a powerful complement, direct chemical editing via monovalent small molecules achieves autonomous, enzyme-independent PTM writing by leveraging inherent chemical reactivity and ligand-directed proximity. Crucially, this strategy extends to broader bioconjugation methods, enabling the installation of PTM mimetics and precise editing of the protein backbone. By synthesizing advances in induced proximity and direct chemical writing, this review provides a framework for developing next-generation precision therapeutics that dynamically edit the PTM landscape.