8K14

X-ray crystal structure of 18a in BRD4(1)

8K14 の概要

• エントリーDOI: 10.2210/pdb8k14/pdb
• 分子名称: Bromodomain-containing protein 4, 4-[8-methoxy-2-methyl-1-(1-phenylethyl)imidazo[4,5-c]quinolin-7-yl]-3,5-dimethyl-1,2-oxazole (3 entities in total)
• 機能のキーワード: brd4(1), bromodomain, protein binding
• 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: 17179.81

構造登録者

Xu, H.,Shen, H.,Zhang, Y.,Xu, Y.,Li, R. (登録日: 2023-07-10, 公開日: 2024-03-27)

主引用文献

Yu, S.,Zhang, Y.,Yang, J.,Xu, H.,Lan, S.,Zhao, B.,Luo, M.,Ma, X.,Zhang, H.,Wang, S.,Shen, H.,Zhang, Y.,Xu, Y.,Li, R.
Discovery of (R)-4-(8-methoxy-2-methyl-1-(1-phenylethy)-1H-imidazo[4,5-c]quinnolin-7-yl)-3,5-dimethylisoxazole as a potent and selective BET inhibitor for treatment of acute myeloid leukemia (AML) guided by FEP calculation.
Eur.J.Med.Chem., 263:115924-115924, 2024

PubMed Abstract: The functions of the bromodomain and extra terminal (BET) family of proteins have been proved to be involved in various diseases, particularly the acute myeloid leukemia (AML). In this work, guided by free energy perturbation (FEP) calculation, a methyl group was selected to be attached to the 1H-imidazo[4,5-c]quinoline skeleton, and a series of congeneric compounds were synthesized. Among them, compound 10 demonstrated outstanding activity against BRD4 BD1 with an IC value of 1.9 nM and exhibited remarkable antiproliferative effects against MV4-11 cells. The X-ray cocrystal structure proved that 10 occupied the acetylated lysine (KAc) binding cavity and the WPF shelf of BRD4 BD1. Additionally, 10 displayed high selectivity towards BET family members, effectively inhibiting the growth of AML cells, promoting apoptosis, and arresting the cell cycle at the G/G phase. Further mechanistic studies demonstrated that compound 10 could suppress the expression of c-Myc and CDK6 while enhancing the expression of P21, PARP, and cleaved PARP. Moreover, 10 exhibited remarkable pharmacokinetic properties and significant antitumor efficacy in vivo. Therefore, compound 10 may represent a new, potent and selective BET bromodomain inhibitor for the development of therapeutics to treat AML.

PubMed: 37992518
DOI: 10.1016/j.ejmech.2023.115924

実験手法

X-RAY DIFFRACTION (1.28 Å)