Degraders are small molecules that facilitate protein destruction through ubiquitination, classified into monovalent molecular glues and bifunctional proteolysis targeting chimeras (PROTACs). While rapid advancements have been made in PROTAC research, glue degraders are less understood due to unclear prerequisites and E3 ligase preferences. Notable glue degraders like thalidomide and its derivatives target CRL4 ligases. The CRL3 family, which includes a wide range of substrate receptors, presents an unresolved opportunity regarding their potential use with glue degraders. Additionally, UM171, relates to hematopoietic stem cell expansion, showing clinical promise but lacking clarity on its action mechanism.
Degraders are small molecules that promote protein degradation through ubiquitination, categorized as monovalent molecular glues and bifunctional PROTACs.
While PROTACs have seen rapid development, glue degraders have lagged due to a lack of understanding of their functional requirements.
The best known glue degraders like thalidomide utilize CUL4-RING ligases, raising curiosity if other ligases, like CRL3s, can be similarly utilized.
UM171, important for expanding haematopoietic stem cells, shows promise in clinical applications, though its precise mechanism remains to be fully understood.
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