7W3D

Crystal structure of BRD4 bromodomain 1 (BD1) in complex with N2-(1,2,3-benzotriazol-5-yl)-N3-(dimethylsulfamoyl)-N6-[(2S)-1-methoxypropan-2-yl]pyridine-2,3,6-triamine

7W3D の概要

• エントリーDOI: 10.2210/pdb7w3d/pdb
• 分子名称: Bromodomain-containing protein 4, N2-(1,2,3-benzotriazol-5-yl)-N3-(dimethylsulfamoyl)-N6-[(2S)-1-methoxypropan-2-yl]pyridine-2,3,6-triamine (3 entities in total)
• 機能のキーワード: protein-inhibitor complex, transcription
• 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: 15445.72

構造登録者

Park, T.H.,Lee, B.I. (登録日: 2021-11-25, 公開日: 2022-09-07, 最終更新日: 2023-11-29)

主引用文献

Pandit, N.,Yoo, M.,Hyun Park, T.,Kim, J.,Mi Kim, S.,Myung Lee, K.,Kim, Y.,Min Bong, S.,Il Lee, B.,Jung, K.Y.,Hoon Park, C.
Discovery of BET specific bromodomain inhibitors with a novel scaffold.
Bioorg.Med.Chem., 72:116967-116967, 2022

PubMed Abstract: Bromodomain and extra-terminal domain (BET) proteins have been considered as potent candidates for anti-cancer drug development. As epigenetic readers, they modulate gene expression by recognizing acetylated lysine residues on histones. Therefore, the pharmacological inhibition of BET proteins has been extensively studied. Herein, we report the novel chemical scaffold of N-(pyridin-2-yl)-1H-benzo[d][1,2,3]triazol-5-amine as BET inhibitors using high-throughput screening assay. Through the analysis of structure-activity relationships, we developed a potent novel compound, which exhibited a better IC value about 2-fold compared to iBet762 against the BRD4 bromodomain (BD). The addition of a sulfonyl group to the pyridine ring enhanced the inhibitory activity. Structural studies showed a clear electron density map for the inhibitor and revealed the structural basis for the critical role of the sulfonyl group in the interaction with BRD4.

PubMed: 36099719
DOI: 10.1016/j.bmc.2022.116967

実験手法

X-RAY DIFFRACTION (1.98 Å)