5OMG

p38alpha in complex with pyrazolobenzothiazine inhibitor COXP4M12

Summary for 5OMG

• Entry DOI: 10.2210/pdb5omg/pdb
• Descriptor: Mitogen-activated protein kinase 14, octyl beta-D-glucopyranoside, 3-(4-fluorophenyl)-4-methyl-1~{H}-pyrazolo[4,3-c][1,2]benzothiazine 5,5-dioxide, ... (4 entities in total)
• Functional Keywords: p38, kinase, inhibitor, pyrazolobenzothiazine, complex, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 41964.91

Authors

Buehrmann, M.,Rauh, D. (deposition date: 2017-07-31, release date: 2019-03-13, Last modification date: 2024-05-08)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2 Å)