6YQS

BRD9 with methylpiperazinyl-benzyl-amino-dimethylpyridazinone

これはPDB形式変換不可エントリーです。

6YQS の概要

• エントリーDOI: 10.2210/pdb6yqs/pdb
• 分子名称: Bromodomain-containing protein 9, 2,4-dimethyl-5-[[2-(4-methylpiperazin-1-yl)phenyl]methylamino]pyridazin-3-one (3 entities in total)
• 機能のキーワード: brd9, inhibitor, histone, epigenetic reader, bromodomain, 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: 12555.63

構造登録者

Chung, C. (登録日: 2020-04-18, 公開日: 2021-03-24, 最終更新日: 2024-05-15)

主引用文献

Clegg, M.A.,Bamborough, P.,Chung, C.W.,Craggs, P.D.,Gordon, L.,Grandi, P.,Leveridge, M.,Lindon, M.,Liwicki, G.M.,Michon, A.M.,Molnar, J.,Rioja, I.,Soden, P.E.,Theodoulou, N.H.,Werner, T.,Tomkinson, N.C.O.,Prinjha, R.K.,Humphreys, P.G.
Application of Atypical Acetyl-lysine Methyl Mimetics in the Development of Selective Inhibitors of the Bromodomain-Containing Protein 7 (BRD7)/Bromodomain-Containing Protein 9 (BRD9) Bromodomains.
J.Med.Chem., 63:5816-5840, 2020

PubMed Abstract: Non-BET bromodomain-containing proteins have become attractive targets for the development of novel therapeutics targeting epigenetic pathways. To help facilitate the target validation of this class of proteins, structurally diverse small-molecule ligands and methodologies to produce selective inhibitors in a predictable fashion are in high demand. Herein, we report the development and application of atypical acetyl-lysine (KAc) methyl mimetics to take advantage of the differential stability of conserved water molecules in the bromodomain binding site. Discovery of the -butyl group as an atypical KAc methyl mimetic allowed generation of (GSK6776) as a soluble, permeable, and selective BRD7/9 inhibitor from a pyridazinone template. The -butyl group was then used to enhance the bromodomain selectivity of an existing BRD9 inhibitor and to transform pan-bromodomain inhibitors into BRD7/9 selective compounds. Finally, a solvent-exposed vector was defined from the pyridazinone template to enable bifunctional molecule synthesis, and affinity enrichment chemoproteomic experiments were used to confirm several of the endogenous protein partners of BRD7 and BRD9, which form part of the chromatin remodeling PBAF and BAF complexes, respectively.

PubMed: 32410449
DOI: 10.1021/acs.jmedchem.0c00075

実験手法

X-RAY DIFFRACTION (1.683 Å)