AI Article Synopsis
- - The discovery of cereblon (CRBN) as the target of thalidomide transformed the targeted protein degradation (TPD) field by introducing bivalent degraders that utilize ubiquitin-mediated pathways.
- - Recently, low-molecular-weight molecular glue degraders (MGDs) have emerged, providing a new approach to TPD with beneficial properties suited for small-molecule treatments.
- - This review explores the development of MGDs, including specific case studies and design principles, while also discussing the collaborative innovations within the chemical space of molecular glues.
Article Abstract
The discovery of the E3 ligase cereblon (CRBN) as the target of thalidomide and its analogs revolutionized the field of targeted protein degradation (TPD). This ubiquitin-mediated degradation pathway was first harnessed by bivalent degraders. Recently, the emergence of low-molecular-weight molecular glue degraders (MGDs) has expanded the TPD landscape, because MGDs operate via the same mechanism while offering attractive physicochemical properties that are consistent with small-molecule therapeutics. This review delves into the discovery and advancement of MGDs, with case studies on cyclin K and the zinc finger protein IKZF2, highlighting the design principles, biological assays and therapeutic applications. Additionally, it examines the chemical space of molecular glues and outlines the collaborative efforts that are fueling innovation in this field.
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| http://dx.doi.org/10.1016/j.drudis.2024.104205 | DOI Listing |
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