Modular Assembled Targeting Chimera Enables Multimodal Targeted Protein Degradation
Wentao Zhu, Wenqian Zhang, Yinmiao Wang, Jian Chen, Fang Xu, Jiyan Pang
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.
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…
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Taxonomy
TopicsProtein Degradation and Inhibitors · Click Chemistry and Applications · Histone Deacetylase Inhibitors Research