2HY0

crystal structure of chek1 in complex with inhibitor 22

2HY0 の概要

• エントリーDOI: 10.2210/pdb2hy0/pdb
• 関連するPDBエントリー: 2HXL 2HXQ
• 分子名称: Serine/threonine-protein kinase Chk1, 3-[5-(PIPERIDIN-1-YLMETHYL)-1H-INDOL-2-YL]-6-(1H-PYRAZOL-4-YL)QUINOLIN-2(1H)-ONE (3 entities in total)
• 機能のキーワード: chek1, kinase, cell cycle checkpoint, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus: O14757
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37214.47

構造登録者

Yan, Y. (登録日: 2006-08-04, 公開日: 2007-06-19, 最終更新日: 2023-08-30)

主引用文献

Huang, S.,Garbaccio, R.M.,Fraley, M.E.,Steen, J.,Kreatsoulas, C.,Hartman, G.,Stirdivant, S.,Drakas, B.,Rickert, K.,Walsh, E.,Hamilton, K.,Buser, C.A.,Hardwick, J.,Mao, X.,Abrams, M.,Beck, S.,Tao, W.,Lobell, R.,Sepp-Lorenzino, L.,Yan, Y.,Ikuta, M.,Murphy, J.Z.,Sardana, V.,Munshi, S.,Kuo, L.,Reilly, M.,Mahan, E.
Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors.
Bioorg.Med.Chem.Lett., 16:5907-5912, 2006

PubMed Abstract: Through a comparison of X-ray co-crystallographic data for 1 and 2 in the Chek1 active site, it was hypothesized that the affinity of the indolylquinolinone series (2) for Chek1 kinase would be improved via C6 substitution into the hydrophobic region I (HI) pocket. An efficient route to 6-bromo-3-indolyl-quinolinone (9) was developed, and this series was rapidly optimized for potency by modification at C6. A general trend was observed among these low nanomolar Chek1 inhibitors that compounds with multiple basic amines, or elevated polar surface area (PSA) exhibited poor cell potency. Minimization of these parameters (basic amines, PSA) resulted in Chek1 inhibitors with improved cell potency, and preliminary pharmacokinetic data are presented for several of these compounds.

PubMed: 16990002
DOI: 10.1016/j.bmcl.2006.08.053

実験手法

X-RAY DIFFRACTION (1.7 Å)