Modular Assembled Targeting Chimera Enables Multimodal Targeted Protein Degradation

Targeted protein degradation (TPD) has emerged as a promising therapeutic strategy, with advantages over traditional protein inhibition. Despite significant advancements in novel degraders such as bivalents and multitargeting proteolysis-targeting chimeras (PROTACs), key challenges persist in the development pipeline, particularly regarding the identification of highly potent degraders and the optimization of their drug-like properties. Here, we reported a multimodal modular assembled targeting chimera (multi-MOATAC) strategy that enabled intracellular click chemistry-mediated <i>in situ</i> assembly of ligand modules with targets, integrating multiple functional units into binary/ternary complexes. This strategy validated significantly enhanced degradation efficiency via trivalent self-assembling degraders and identified a highly effective self-assembly stoichiometric ratio, achieving a DC₅₀ of 4.6 ± 1.3 nM for BRD4 in MDA-MB-231 cells. To evaluate broad applicability, the target scope was expanded from nuclear protein BRD4 to challenging targets, including membrane-localized EGFR and cytoplasmic protein ALK. Furthermore, optimizing the stoichiometric ratio of self-assembling modules achieved parallel degradation of distinct targets. The superior antitumor efficacy of trivalent self-assembling PROTACs was also confirmed <i>in vivo</i>. The highly modular and scalable multi-MOATAC strategy may enable broad applications in developing novel tissue-specific degraders and advancing therapeutics for related diseases.