4YAD

Crystal structure of TRIM24 PHD-bromodomain complexed with 2,4-dimethoxy-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)benzene-1-sulfonamide (3b)

4YAD の概要

• エントリーDOI: 10.2210/pdb4yad/pdb
• 関連するPDBエントリー: 4YAB 4YAT 4YAX 4YBM 4YBS 4YBT
• 分子名称: Transcription intermediary factor 1-alpha, ZINC ION, 2,4-dimethoxy-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)benzenesulfonamide, ... (6 entities in total)
• 機能のキーワード: center for biomolecular structure and function, bromodomain, trim24, inhibitor, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus : O15164
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 43906.37

構造登録者

Poncet-Montange, G.,Palmer, W.,Jones, P. (登録日: 2015-02-17, 公開日: 2015-06-24, 最終更新日: 2023-09-27)

主引用文献

Palmer, W.S.,Poncet-Montange, G.,Liu, G.,Petrocchi, A.,Reyna, N.,Subramanian, G.,Theroff, J.,Yau, A.,Kost-Alimova, M.,Bardenhagen, J.P.,Leo, E.,Shepard, H.E.,Tieu, T.N.,Shi, X.,Zhan, Y.,Zhao, S.,Barton, M.C.,Draetta, G.,Toniatti, C.,Jones, P.,Geck Do, M.,Andersen, J.N.
Structure-Guided Design of IACS-9571, a Selective High-Affinity Dual TRIM24-BRPF1 Bromodomain Inhibitor.
J.Med.Chem., 59:1440-1454, 2016

PubMed Abstract: The bromodomain containing proteins TRIM24 (tripartite motif containing protein 24) and BRPF1 (bromodomain and PHD finger containing protein 1) are involved in the epigenetic regulation of gene expression and have been implicated in human cancer. Overexpression of TRIM24 correlates with poor patient prognosis, and BRPF1 is a scaffolding protein required for the assembly of histone acetyltransferase complexes, where the gene of MOZ (monocytic leukemia zinc finger protein) was first identified as a recurrent fusion partner in leukemia patients (8p11 chromosomal rearrangements). Here, we present the structure guided development of a series of N,N-dimethylbenzimidazolone bromodomain inhibitors through the iterative use of X-ray cocrystal structures. A unique binding mode enabled the design of a potent and selective inhibitor 8i (IACS-9571) with low nanomolar affinities for TRIM24 and BRPF1 (ITC Kd = 31 nM and ITC Kd = 14 nM, respectively). With its excellent cellular potency (EC50 = 50 nM) and favorable pharmacokinetic properties (F = 29%), 8i is a high-quality chemical probe for the evaluation of TRIM24 and/or BRPF1 bromodomain function in vitro and in vivo.

PubMed: 26061247
DOI: 10.1021/acs.jmedchem.5b00405

実験手法

X-RAY DIFFRACTION (1.73 Å)