7RWO

Crystal Structure of BPTF bromodomain in complex with 4-chloro-2-methyl-5-[(1,2,3,4-tetrahydroisoquinolin-7-yl)amino]pyridazin-3(2H)-one

7RWO の概要

• エントリーDOI: 10.2210/pdb7rwo/pdb
• 分子名称: Nucleosome-remodeling factor subunit BPTF, 4-chloro-2-methyl-5-[(1,2,3,4-tetrahydroisoquinolin-7-yl)amino]pyridazin-3(2H)-one, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: brd4, gene regulation, gene regulation-inhibitor complex, gene regulation/inhibitor
• 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: 15823.31

構造登録者

Zahid, H.,Buchholz, C.,Johnson, J.A.,Shi, K.,Aihara, H.,Pomerantz, W.C.K. (登録日: 2021-08-20, 公開日: 2022-08-24, 最終更新日: 2023-10-18)

主引用文献

Zahid, H.,Buchholz, C.R.,Singh, M.,Ciccone, M.F.,Chan, A.,Nithianantham, S.,Shi, K.,Aihara, H.,Fischer, M.,Schonbrunn, E.,Dos Santos, C.O.,Landry, J.W.,Pomerantz, W.C.K.
New Design Rules for Developing Potent Cell-Active Inhibitors of the Nucleosome Remodeling Factor (NURF) via BPTF Bromodomain Inhibition.
J.Med.Chem., 64:13902-13917, 2021

PubMed Abstract: The nucleosome remodeling factor (NURF) alters chromatin accessibility through interactions with its largest subunit,the bromodomain PHD finger transcription factor BPTF. BPTF is overexpressed in several cancers and is an emerging anticancer target. Targeting the BPTF bromodomain presents a potential strategy for its inhibition and the evaluation of its functional significance; however, inhibitor development for BPTF has lagged behind those of other bromodomains. Here we describe the development of pyridazinone-based BPTF inhibitors. The lead compound, , possesses a high potency ( = 6.3 nM) and >350-fold selectivity over BET bromodomains. We identify an acidic triad in the binding pocket to guide future designs. We show that our inhibitors sensitize 4T1 breast cancer cells to doxorubicin but not BPTF knockdown cells, suggesting a specificity to BPTF. Given the high potency and good physicochemical properties of these inhibitors, we anticipate that they will be useful starting points for chemical tool development to explore the biological roles of BPTF.

PubMed: 34515477
DOI: 10.1021/acs.jmedchem.1c01294

実験手法

X-RAY DIFFRACTION (1.58 Å)