6WWB

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

6WWB の概要

• エントリーDOI: 10.2210/pdb6wwb/pdb
• 分子名称: 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)
• 機能のキーワード: bet, brd2, bromodomain, inhibitor, complex, transcription, protac
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 14576.04

構造登録者

White, S.W.,Yun, M. (登録日: 2020-05-08, 公開日: 2021-11-17, 最終更新日: 2023-10-18)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.31 Å)