3L9H

X-ray structure of mitotic kinesin-5 (KSP, KIF11, Eg5)in complex with the hexahydro-2H-pyrano[3,2-c]quinoline EMD 534085

Summary for 3L9H

• Entry DOI: 10.2210/pdb3l9h/pdb
• Descriptor: Kinesin-like protein KIF11, ADENOSINE-5'-DIPHOSPHATE, 1-[2-(dimethylamino)ethyl]-3-{[(2R,4aS,5R,10bS)-5-phenyl-9-(trifluoromethyl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-yl]methyl}urea, ... (4 entities in total)
• Functional Keywords: mitotic spindle kinesin, eg5, small molecule inhibitor, emd 534085, acetylation, atp-binding, cell cycle, cell division, coiled coil, microtubule, mitosis, motor protein, nucleotide-binding, phosphoprotein, polymorphism
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P52732
• Total number of polymer chains: 2
• Total formula weight: 83918.63

Authors

Knoechel, T. (deposition date: 2010-01-05, release date: 2010-03-02, Last modification date: 2024-03-20)

Primary citation

Schiemann, K.,Finsinger, D.,Zenke, F.,Amendt, C.,Knochel, T.,Bruge, D.,Buchstaller, H.P.,Emde, U.,Stahle, W.,Anzali, S.
The discovery and optimization of hexahydro-2H-pyrano[3,2-c]quinolines (HHPQs) as potent and selective inhibitors of the mitotic kinesin-5.
Bioorg.Med.Chem.Lett., 20:1491-1495, 2010

PubMed Abstract: Here we describe the discovery and optimization of hexahydro-2H-pyrano[3,2-c]quinolines (HHPQs) as potent and selective inhibitors of the mitotic kinesin-5 originally found during a high-throughput screening (HTS) campaign sampling our in-house compound collection. The compounds optimized subsequently and characterized herein were potently inhibiting the ATPase activity of Kinesin-5 and also exhibited consistent cellular activity, in that cells arrested in mitosis and apoptosis induction could be observed. X-ray crystallographic data demonstrated that these inhibitors bind in an allosteric pocket of Kinesin-5 distant from the nucleotide and microtubule binding sites. The selected clinical candidate EMD 534085 caused strong growth inhibition in human tumor xenograft models using Colo 205 colon carcinoma cells at doses below 30mg/kg administered twice weekly without showing severe toxicity as determined by loss of body weight.

PubMed: 20149654
DOI: 10.1016/j.bmcl.2010.01.110

Experimental method

X-RAY DIFFRACTION (2 Å)