Molecular glue-mediated targeted protein degradation: A novel strategy in small-molecule drug development

Small-molecule drugs are effective and thus most widely used. However, their applications are limited by their reliance on active high-affinity binding sites, restricting their target options. A breakthrough approach involves molecular glues, a novel class of small-molecule compounds capable of indu...

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Bibliographic Details
Published in:iScience 2024-09, Vol.27 (9), p.110712, Article 110712
Main Authors: Tan, Xueqiang, Huang, Zuyi, Pei, Hairun, Jia, Zongchao, Zheng, Jimin
Format: Article
Language:English
Subjects:
Applied chemistry
Biochemistry
Biological sciences
Chemistry
Natural sciences
Review
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Summary:Small-molecule drugs are effective and thus most widely used. However, their applications are limited by their reliance on active high-affinity binding sites, restricting their target options. A breakthrough approach involves molecular glues, a novel class of small-molecule compounds capable of inducing protein-protein interactions (PPIs). This opens avenues to target conventionally undruggable proteins, overcoming limitations seen in conventional small-molecule drugs. Molecular glues play a key role in targeted protein degradation (TPD) techniques, including ubiquitin-proteasome system-based approaches such as proteolysis targeting chimeras (PROTACs) and molecular glue degraders and recently emergent lysosome system-based techniques like molecular degraders of extracellular proteins through the asialoglycoprotein receptors (MoDE-As) and macroautophagy degradation targeting chimeras (MADTACs). These techniques enable an innovative targeted degradation strategy for prolonged inhibition of pathology-associated proteins. This review provides an overview of them, emphasizing the clinical potential of molecular glues and guiding the development of molecular-glue-mediated TPD techniques. [Display omitted] Natural sciences; Chemistry; Applied chemistry; Biological sciences; Biochemistry
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2024.110712