4BYI

Aurora A kinase bound to a highly selective imidazopyridine inhibitor

4BYI の概要

• エントリーDOI: 10.2210/pdb4byi/pdb
• 関連するPDBエントリー: 4BYJ
• 分子名称: AURORA KINASE A, (S)-N-((1-(6-chloro-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)pyrrolidin-3-yl)methyl)acetamide (2 entities in total)
• 機能のキーワード: transferase, cell cycle, inhibitor
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome: O14965
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33336.65

構造登録者

Joshi, A.,Kosmopoulou, M.,Bayliss, R. (登録日: 2013-07-19, 公開日: 2013-11-20, 最終更新日: 2023-12-20)

主引用文献

Bavetsias, V.,Faisal, A.,Crumpler, S.,Brown, N.,Kosmopoulou, M.,Joshi, A.,Atrash, B.,Perez-Fuertes, Y.,Schmitt, J.A.,Boxall, K.J.,Burke, R.,Sun, C.,Avery, S.,Bush, K.,Henley, A.,Raynaud, F.I.,Workman, P.,Bayliss, R.,Linardopoulos, S.,Blagg, J.
Aurora Isoform Selectivity: Design and Synthesis of Imidazo[4,5-B]Pyridine Derivatives as Highly Selective Inhibitors of Aurora-A Kinase in Cells.
J.Med.Chem., 56:9122-, 2013

PubMed Abstract: Aurora-A differs from Aurora-B/C at three positions in the ATP-binding pocket (L215, T217, and R220). Exploiting these differences, crystal structures of ligand-Aurora protein interactions formed the basis of a design principle for imidazo[4,5-b]pyridine-derived Aurora-A-selective inhibitors. Guided by a computational modeling approach, appropriate C7-imidazo[4,5-b]pyridine derivatization led to the discovery of highly selective inhibitors, such as compound 28c, of Aurora-A over Aurora-B. In HCT116 human colon carcinoma cells, 28c and 40f inhibited the Aurora-A L215R and R220K mutants with IC50 values similar to those seen for the Aurora-A wild type. However, the Aurora-A T217E mutant was significantly less sensitive to inhibition by 28c and 40f compared to the Aurora-A wild type, suggesting that the T217 residue plays a critical role in governing the observed isoform selectivity for Aurora-A inhibition. These compounds are useful small-molecule chemical tools to further explore the function of Aurora-A in cells.

PubMed: 24195668
DOI: 10.1021/JM401115G

実験手法

X-RAY DIFFRACTION (2.6 Å)