3DS6

P38 complex with a phthalazine inhibitor

3DS6 の概要

• エントリーDOI: 10.2210/pdb3ds6/pdb
• 分子名称: Mitogen-activated protein kinase 14, N-cyclopropyl-4-methyl-3-[1-(2-methylphenyl)phthalazin-6-yl]benzamide (2 entities in total)
• 機能のキーワード: kinase inhibitor complex, alternative splicing, atp-binding, cytoplasm, kinase, nucleotide-binding, nucleus, phosphoprotein, polymorphism, serine/threonine-protein kinase, transferase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm (By similarity): Q16539
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 169569.67

構造登録者

Herberich, B.,Syed, R.,Li, V.,Grosfeld, D. (登録日: 2008-07-11, 公開日: 2008-10-07, 最終更新日: 2024-04-03)

主引用文献

Herberich, B.,Cao, G.Q.,Chakrabarti, P.P.,Falsey, J.R.,Pettus, L.,Rzasa, R.M.,Reed, A.B.,Reichelt, A.,Sham, K.,Thaman, M.,Wurz, R.P.,Xu, S.,Zhang, D.,Hsieh, F.,Lee, M.R.,Syed, R.,Li, V.,Grosfeld, D.,Plant, M.H.,Henkle, B.,Sherman, L.,Middleton, S.,Wong, L.M.,Tasker, A.S.
Discovery of highly selective and potent p38 inhibitors based on a phthalazine scaffold.
J.Med.Chem., 51:6271-6279, 2008

PubMed Abstract: Investigations into the structure-activity relationships (SAR) of a series of phthalazine-based inhibitors of p38 are described. These efforts originated from quinazoline 1 and through rational design led to the development of a series of orally bioavailable, potent, and selective inhibitors. Kinase selectivity was achieved by exploiting a collection of interactions with p38alpha including close contact to Ala157, occupation of the hydrophobic gatekeeper pocket, and a residue flip with Gly110. Substitutions on the phthalazine influenced the pharmacokinetic properties, of which compound 16 displayed the most desirable profile. Oral dosing (0.03 mg/kg) of 16 in rats 1 h prior to LPS challenge gave a >50% decrease in TNFalpha production.

PubMed: 18817365
DOI: 10.1021/jm8005417

実験手法

X-RAY DIFFRACTION (2.9 Å)