2ZDT

Crystal Structure of human JNK3 complexed with an isoquinolone inhibitor

Summary for 2ZDT

• Entry DOI: 10.2210/pdb2zdt/pdb
• Related: 2ZDU
• Descriptor: Mitogen-activated protein kinase 10, 4-[(6-chloro-1-oxo-4-phenyl-3-propanoylisoquinolin-2(1H)-yl)methyl]benzoic acid, GLYCEROL, ... (4 entities in total)
• Functional Keywords: protein kinase, atp-binding, epilepsy, nucleotide-binding, phosphoprotein, serine/threonine-protein kinase, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P53779
• Total number of polymer chains: 1
• Total formula weight: 42597.66

Authors

Sogabe, S.,Asano, Y.,Fukumoto, S.,Habuka, N.,Fujishima, A. (deposition date: 2007-11-27, release date: 2008-09-23, Last modification date: 2023-11-01)

Primary citation

Asano, Y.,Kitamura, S.,Ohra, T.,Itoh, F.,Kajino, M.,Tamura, T.,Kaneko, M.,Ikeda, S.,Igata, H.,Kawamoto, T.,Sogabe, S.,Matsumoto, S.,Tanaka, T.,Yamaguchi, M.,Kimura, H.,Fukumoto, S.
Discovery, synthesis and biological evaluation of isoquinolones as novel and highly selective JNK inhibitors (2)
Bioorg.Med.Chem., 16:4699-4714, 2008

PubMed Abstract: 3-Metoxycarbonyl isoquinolone derivative 1 has been identified as a potent JNK inhibitor and significantly inhibited cardiac hypertrophy in a rat pressure-overload model. Herein, a series of isoquinolones with an imidazolylmethyl or a pyrazolylmethyl group at the 2-position were designed based on X-ray crystallographic analysis of the complex between the isoquinolone compound and JNK3, as wells as the relationship between compound lipophilicity (logD) and activity in a cell-based assay. The compounds prepared showed potent JNK1 inhibitory activities in a cell-based assay. Among them the isoquinolone derivative possessing 5-[(cyclopropylamino)carbonyl]-1-methyl-1H-pyrazole (16e) exhibited significant anti-hypertrophic activity at doses of more than 1mg/kg (po) in a pressure-overload model.

PubMed: 18313930
DOI: 10.1016/j.bmc.2008.02.028

Experimental method

X-RAY DIFFRACTION (2 Å)