2HY0

crystal structure of chek1 in complex with inhibitor 22

Summary for 2HY0

• Entry DOI: 10.2210/pdb2hy0/pdb
• Related: 2HXL 2HXQ
• Descriptor: 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)
• Functional Keywords: chek1, kinase, cell cycle checkpoint, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: O14757
• Total number of polymer chains: 1
• Total formula weight: 37214.47

Authors

Yan, Y. (deposition date: 2006-08-04, release date: 2007-06-19, Last modification date: 2023-08-30)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.7 Å)