# Modular Assembled Targeting Chimera Enables Multimodal Targeted Protein Degradation

## TL;DR

A new modular strategy for targeted protein degradation improves drug efficiency and expands target reach.

## Contribution

Introduces multi-MOATAC, a modular chimera strategy for efficient and multimodal protein degradation.

## Key findings

- Trivalent self-assembling degraders achieved a DC50 of 4.6 ± 1.3 nM for BRD4 in MDA-MB-231 cells.
- Strategy successfully targeted membrane-localized EGFR and cytoplasmic ALK proteins.
- In vivo antitumor efficacy confirmed for trivalent self-assembling PROTACs.

## Abstract

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 in situ 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 in vivo. The highly modular and scalable multi-MOATAC strategy
may enable broad applications in developing novel tissue-specific
degraders and advancing therapeutics for related diseases.