3M2W

Crystal structure of MAPKAK kinase 2 (MK2) complexed with a spiroazetidine-tetracyclic ATP site inhibitor

Summary for 3M2W

• Entry DOI: 10.2210/pdb3m2w/pdb
• Related: 3KGA
• Descriptor: MAP kinase-activated protein kinase 2, 2'-(2-fluorophenyl)-1-methyl-6',8',9',11'-tetrahydrospiro[azetidine-3,10'-pyrido[3',4':4,5]pyrrolo[2,3-f]isoquinolin]-7'(5'H)-one, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: small molecule inhibitor, spiroazetidine-tetracycle, atp-site kinase inhibitor, novartis compound nvp-bxs169, atp-binding, kinase, nucleotide-binding, phosphoprotein, serine/threonine-protein kinase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 34976.78

Authors

Kroemer, M.,Revesz, L.,Be, C.,Izaac, A.,Huppertz, C.,Schlapbach, A.,Scheufler, C. (deposition date: 2010-03-08, release date: 2010-07-28, Last modification date: 2024-02-21)

Primary citation

Revesz, L.,Schlapbach, A.,Aichholz, R.,Dawson, J.,Feifel, R.,Hawtin, S.,Littlewood-Evans, A.,Koch, G.,Kroemer, M.,Mobitz, H.,Scheufler, C.,Velcicky, J.,Huppertz, C.
In vivo and in vitro SAR of tetracyclic MAPKAP-K2 (MK2) inhibitors. Part II.
Bioorg.Med.Chem.Lett., 20:4719-4723, 2010

PubMed Abstract: Spirocyclopropane- and spiroazetidine-substituted tetracycles 13D-E and 16A are described as orally active MK2 inhibitors. The spiroazetidine derivatives are potent MK2 inhibitors with IC(50)<3 nM and inhibit the release of TNFalpha (IC(50)<0.3 microM) from hPBMCs and hsp27 phosphorylation in anisomycin stimulated THP-1 cells. The spirocyclopropane analogues are less potent against MK2 (IC(50)=0.05-0.23 microM), less potent in cells (IC(50)<1.1 microM), but show good oral absorption. Compound 13E (100mg/kg po; bid) showed oral activity in rAIA and mCIA, with significant reduction of swelling and histological score.

PubMed: 20591669
DOI: 10.1016/j.bmcl.2010.04.023

Experimental method

X-RAY DIFFRACTION (2.41 Å)