3ITZ

Crystal Structure of p38a Mitogen-Activated Protein Kinase in Complex with a Pyrazolopyridazine Inhibitor

3ITZ の概要

• エントリーDOI: 10.2210/pdb3itz/pdb
• 関連するPDBエントリー: 1YQJ 3DS6 3DT1 3GFE
• 分子名称: Mitogen-activated protein kinase 14, 4-chloro-N-cyclopropyl-3-{[1-(2,6-difluorophenyl)-1H-pyrazolo[3,4-d]pyridazin-4-yl]amino}benzamide (3 entities in total)
• 機能のキーワード: serine/threonine-protein kinase, transferase, alternative splicing, atp-binding, cytoplasm, kinase, nucleotide-binding, nucleus, phosphoprotein, polymorphism
• 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: 1
• 化学式量合計: 42439.77

構造登録者

Mohr, C.,Jordan, S. (登録日: 2009-08-28, 公開日: 2010-03-02, 最終更新日: 2024-02-21)

主引用文献

Wurz, R.P.,Pettus, L.H.,Henkle, B.,Sherman, L.,Plant, M.,Miner, K.,McBride, H.J.,Wong, L.M.,Saris, C.J.,Lee, M.R.,Chmait, S.,Mohr, C.,Hsieh, F.,Tasker, A.S.
Part 2: Structure-activity relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38alpha mitogen-activated protein kinase.
Bioorg.Med.Chem.Lett., 20:1680-1684, 2010

PubMed Abstract: A novel class of pyrazolopyridazine p38alpha mitogen-activated protein kinase (MAPK) inhibitors is disclosed. A structure activity relationship (SAR) investigation was conducted driven by the ability of these compounds to inhibit the p38alpha enzyme, the secretion of TNFalpha in a LPS-challenged THP1 cell line and TNFalpha-induced production of IL-8 in the presence of 50% human whole blood (hWB). This study resulted in the discovery of several inhibitors with IC(50) values in the single-digit nanomolar range in hWB. Further investigation of the pharmacokinetic profiles of these lead compounds led to the identification of three potent and orally bioavailable p38alpha inhibitors 2h, 2m, and 13h. Inhibitor 2m was found to be highly selective for p38alpha/beta over a panel of 402 other kinases in Ambit screening, and was highly efficacious in vivo in the inhibition of TNFalpha production in LPS-stimulated Lewis rats with an ED(50) of ca. 0.08mg/kg.

PubMed: 20138761
DOI: 10.1016/j.bmcl.2010.01.059

実験手法

X-RAY DIFFRACTION (2.25 Å)