6MAU

Crystal structure of human BRD4(1) in complex with CN210 (compound 19)

6MAU の概要

• エントリーDOI: 10.2210/pdb6mau/pdb
• 分子名称: Bromodomain-containing protein 4, 1-(4-{6-(3,5-dimethyl-1,2-oxazol-4-yl)-4-[(3S)-3-phenylmorpholin-4-yl]quinazolin-2-yl}-1H-pyrazol-1-yl)-2-methylpropan-2-ol, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: brd4(1), 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: 15946.30

構造登録者

Nadupalli, A.,Fontano, E.,Connors, C.R.,Chan, S.G.,Olland, A.M.,Lakshminarasimhan, D.,White, A.,Suto, R.K. (登録日: 2018-08-28, 公開日: 2019-04-03, 最終更新日: 2024-03-13)

主引用文献

Yang, S.M.,Yoshioka, M.,Strovel, J.W.,Urban, D.J.,Hu, X.,Hall, M.D.,Jadhav, A.,Maloney, D.J.
Lead optimization and efficacy evaluation of quinazoline-based BET family inhibitors for potential treatment of cancer and inflammatory diseases.
Bioorg. Med. Chem. Lett., 29:1220-1226, 2019

PubMed Abstract: Extensive optimization of quinazoline-based lead 8 is described. The structure-activity relationship studies indicate the S-configuration is preferred for the phenylmorpholine substitution. Together with incorporation of a (2-hydroxyl-2-methylpropyl)pyrazole moiety at the 2-position leads to analogs with comparable potency and marked improvement in the pharmacokinetic profile over our previously reported lead compounds. Further in vivo efficacy studies in Kasumi-1 xenograft mouse model demonstrates that the selected inhibitors are well tolerated and highly efficacious in the inhibition of tumor growth. Additionally, the representative analog 19 also demonstrated significant improvement of arthritis severity in a collagen-induced arthritis (CIA) mouse model. These results indicate potential use of these quinazoline-based BET inhibitors for treatment of cancer and inflammatory diseases. A brief discussion of the co-crystallized structure of 19 with BRD4 (BD1) is also highlighted.

PubMed: 30905542
DOI: 10.1016/j.bmcl.2019.03.014

実験手法

X-RAY DIFFRACTION (2.11 Å)