6WWB

Crystal Structure of the second bromodomain of human BRD2 in complex with the compound 3b

Summary for 6WWB

• Entry DOI: 10.2210/pdb6wwb/pdb
• Descriptor: Bromodomain-containing protein 2, 1,2-ETHANEDIOL, 2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-((1-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamido)butyl)-1H-1,2,3-triazol-4-yl)methyl)acetamide, ... (4 entities in total)
• Functional Keywords: bet, brd2, bromodomain, inhibitor, complex, transcription, protac
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 14576.04

Authors

White, S.W.,Yun, M. (deposition date: 2020-05-08, release date: 2021-11-17, Last modification date: 2023-10-18)

Primary citation

Min, J.,Mayasundari, A.,Keramatnia, F.,Jonchere, B.,Yang, S.W.,Jarusiewicz, J.,Actis, M.,Das, S.,Young, B.,Slavish, J.,Yang, L.,Li, Y.,Fu, X.,Garrett, S.H.,Yun, M.K.,Li, Z.,Nithianantham, S.,Chai, S.,Chen, T.,Shelat, A.,Lee, R.E.,Nishiguchi, G.,White, S.W.,Roussel, M.F.,Potts, P.R.,Fischer, M.,Rankovic, Z.
Phenyl-Glutarimides: Alternative Cereblon Binders for the Design of PROTACs.
Angew.Chem.Int.Ed.Engl., 60:26663-26670, 2021

PubMed Abstract: 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 (IC =3 pM; BRD4 DC =0.87 nM). These findings strongly support the utility of PG derivatives in the design of CRBN-directed PROTACs.

PubMed: 34614283
DOI: 10.1002/anie.202108848

Experimental method

X-RAY DIFFRACTION (1.31 Å)