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

Summary for 7W3D

• Entry DOI: 10.2210/pdb7w3d/pdb
• Descriptor: 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)
• Functional Keywords: protein-inhibitor complex, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 15445.72

Authors

Park, T.H.,Lee, B.I. (deposition date: 2021-11-25, release date: 2022-09-07, Last modification date: 2023-11-29)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.98 Å)