4A9M

N-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH N-cyclopentyl-5-(3,5- dimethyl-1,2-oxazol-4-yl)-2-methylbenzene-1-sulfonamide

4A9M の概要

• エントリーDOI: 10.2210/pdb4a9m/pdb
• 関連するPDBエントリー: 1X0J 2YDW 2YEK 4A9E 4A9F 4A9I 4A9J
• 分子名称: BROMODOMAIN CONTAINING 2, N-cyclopentyl-5-(3,5-dimethylisoxazol-4-yl)-2-methylbenzenesulfonamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: inhibitor, histone, epigenetic reader, signaling protein
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Nucleus (By similarity): P25440
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 55017.67

構造登録者

Chung, C.,Bamborough, P. (登録日: 2011-11-26, 公開日: 2012-02-08, 最終更新日: 2024-05-08)

主引用文献

Bamborough, P.,Diallo, H.,Goodacre, J.D.,Gordon, L.,Lewis, A.,Seal, J.T.,Wilson, D.M.,Woodrow, M.D.,Chung, C.W.
Fragment-Based Discovery of Bromodomain Inhibitors Part 2: Optimization of Phenylisoxazole Sulfonamides.
J.Med.Chem., 55:587-, 2012

PubMed Abstract: Bromodomains are epigenetic reader modules that regulate gene transcription through their recognition of acetyl-lysine modified histone tails. Inhibitors of this protein-protein interaction have the potential to modulate multiple diseases as demonstrated by the profound anti-inflammatory and antiproliferative effects of a recently disclosed class of BET compounds. While these compounds were discovered using phenotypic assays, here we present a highly efficient alternative approach to find new chemical templates, exploiting the abundant structural knowledge that exists for this target class. A phenyl dimethyl isoxazole chemotype resulting from a focused fragment screen has been rapidly optimized through structure-based design, leading to a sulfonamide series showing anti-inflammatory activity in cellular assays. This proof-of-principle experiment demonstrates the tractability of the BET family and bromodomain target class to fragment-based hit discovery and structure-based lead optimization.

PubMed: 22136469
DOI: 10.1021/JM201283Q

実験手法

X-RAY DIFFRACTION (2.06 Å)