6wwb | pdb_00006wwb
Crystal Structure of the second bromodomain of human BRD2 in complex with the compound 3b
Structural highlights
Function[BRD2_HUMAN] May play a role in spermatogenesis or folliculogenesis (By similarity). Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling. Regulates transcription of the CCND1 gene. Plays a role in nucleosome assembly.[1] Publication Abstract from PubMedTargeting 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 4c (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 (IC 50 = 3 pM; BRD4 DC 50 = 0.87 nM). These findings strongly support the utility of PG derivatives in the design of CRBN-directed PROTACs. Phenyl-Glutarimides: Alternative Cereblon Binders for the Design of PROTACs.,Rankovic Z, Min J, Mayasundari A, Keramatnia F, Jonchere B, Yang SW, Jarusiewicz JA, Actis M, Das S, Young BM, Slavish PJ, Yang L, Li Y, Fu X, Garrett SH, Yun MK, Li Z, Nithianantham S, Chai SC, Chen T, Shelat AA, Lee RE, Nishiguchi G, White SW, Roussel MF, Potts PR, Fischer M Angew Chem Int Ed Engl. 2021 Oct 6. doi: 10.1002/anie.202108848. PMID:34614283[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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