3M2W: Crystal Structure Of Mapkak Kinase 2 (Mk2) Complexed With A Spiroazetidine-Tetracyclic Atp Site Inhibitor

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.
PDB ID: 3M2WDownload
MMDB ID: 83623
PDB Deposition Date: 2010/3/8
Updated in MMDB: 2010/07
Experimental Method:
x-ray diffraction
Resolution: 2.41  Å
Source Organism:
Similar Structures:
Biological Unit for 3M2W: monomeric; determined by author
Molecular Components in 3M2W
Label Count Molecule
Protein (1 molecule)
MAP Kinase-activated Protein Kinase 2(Gene symbol: MAPKAPK2)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

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