期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 60, 期 51, 页码 26663-26670出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202108848
关键词
cereblon; IMiD; PG; phenyl glutarimide; PROTAC
资金
- ALSAC
- St. Jude Children's Research Hospital
- NCI [P01 CA096832, P30 CA021765]
- [1R35GM142772-01]
IMiDs and IMiD-based PROTACs rapidly hydrolyze in commonly utilized cell media, affecting their efficacy; Novel CRBN binders, phenyl glutarimide (PG) analogues, were designed with high affinity and improved stability; Discovery of PG PROTAC 4c as a potent degrader of BET proteins, supporting the utility of PG derivatives in CRBN-directed PROTACs design.
Targeting cereblon (CRBN) is currently one of the most frequently reported proteolysis-targeting chimera (PROTAC) approaches, owing to favorable drug-like properties of CRBN ligands, immunomodulatory imide drugs (IMiDs). However, IMiDs are known to be inherently unstable, readily undergoing hydrolysis in body fluids. Here we show that IMiDs and IMiD-based PROTACs rapidly hydrolyze in commonly utilized cell media, which significantly affects their cell efficacy. We designed novel CRBN binders, phenyl glutarimide (PG) analogues, and showed that they retained affinity for CRBN with high ligand efficiency (LE >0.48) and displayed improved chemical stability. Our efforts led to the discovery of PG PROTAC 4 c (SJ995973), a uniquely potent degrader of bromodomain and extra-terminal (BET) proteins that inhibited the viability of human acute myeloid leukemia MV4-11 cells at low picomolar concentrations (IC50=3 pM; BRD4 DC50=0.87 nM). These findings strongly support the utility of PG derivatives in the design of CRBN-directed PROTACs.
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