5OMH

p38alpha in complex with pyrazolobenzothiazine inhibitor COXH11

5OMH の概要

• エントリーDOI: 10.2210/pdb5omh/pdb
• 分子名称: Mitogen-activated protein kinase 14, 1-(3-chlorophenyl)-3-methyl-4~{H}-pyrazolo[4,3-c][1,2]benzothiazine 5,5-dioxide (3 entities in total)
• 機能のキーワード: p38, kinase, inhibitor, pyrazolobenzothiazine, complex, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 41689.00

構造登録者

Buehrmann, M.,Rauh, D. (登録日: 2017-07-31, 公開日: 2019-03-13, 最終更新日: 2024-05-08)

主引用文献

Bartolini, D.,Buhrmann, M.,Barreca, M.L.,Manfroni, G.,Cecchetti, V.,Rauh, D.,Galli, F.
Co-crystal structure determination and cellular evaluation of 1,4-dihydropyrazolo[4,3-c] [1,2] benzothiazine 5,5-dioxide p38 alpha MAPK inhibitors.
Biochem.Biophys.Res.Commun., 511:579-586, 2019

PubMed Abstract: p38α mitogen-activated protein kinase (MAPK) is an attracting pharmacological target in inflammatory diseases and cancer. Searching for new and more efficient p38-MAPK inhibitors, two recently developed pyrazolobenzothiazine-based (COXP4M12 and COXH11) compounds were investigated in this study using a cellular model of p38 activation. This consisted of HT29 human colorectal adenocarcinoma cells exposed to HO or lipopolysaccharide (LPS). Immunoblot data confirmed the inhibitory effect of COXP4M12 and COXH11 on p38 substrate phosphorylation (MAPK-APK2 and ATF2 transcription factor). Compound cytotoxicity was very low and apparent efficacy of these inhibitors was comparable with that of SB203580, a commercially available type I inhibitor of p38. All these compounds also inhibit upstream kinases that promote p38-MAPK phosphorylation and co-activate the stress-activated protein kinase JNK, while ERK1/2 MAPK phosphorylation was unaffected. Compound-target kinase interaction was investigated by means of co-crystallization experiments that provided further structural and molecular insight on the inhibitory mechanism and optimization strategy of this new class of p38-MAPK inhibitors.

PubMed: 30824186
DOI: 10.1016/j.bbrc.2019.02.063

実験手法

X-RAY DIFFRACTION (2.5 Å)