4CIK

plasminogen kringle 1 in complex with inhibitor

Summary for 4CIK

• Entry DOI: 10.2210/pdb4cik/pdb
• Descriptor: PLASMINOGEN, 5-[(2R,4S)-2-(phenylmethyl)piperidin-4-yl]-1,2-oxazol-3-one (3 entities in total)
• Functional Keywords: hydrolase, fibrinolysis, plasminogen, protein-protein interaction, kringle ligand
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Secreted: P00747
• Total number of polymer chains: 1
• Total formula weight: 9837.87

Authors

Xue, Y.,Johansson, C.,Cheng, L.,Pettersen, D.,Gustafsson, D. (deposition date: 2013-12-10, release date: 2014-06-18, Last modification date: 2024-11-06)

Primary citation

Cheng, L.,Pettersen, D.,Ohlsson, B.,Schell, P.,Karle, M.,Evertsson, E.,Pahlen, S.,Jonforsen, M.,Plowright, A.T.,Bostrom, J.,Fex, T.,Thelin, A.,Hilgendorf, C.,Xue, Y.,Wahlund, G.,Lindberg, W.,Larsson, L.,Gustafsson, D.
Discovery of the Fibrinolysis Inhibitor Azd6564, Acting Via Interference of a Protein-Protein Interaction.
Acs Med.Chem.Lett., 5:538-, 2014

PubMed Abstract: A class of novel oral fibrinolysis inhibitors has been discovered, which are lysine mimetics containing an isoxazolone as a carboxylic acid isostere. As evidenced by X-ray crystallography the inhibitors bind to the lysine binding site in plasmin thus preventing plasmin from binding to fibrin, hence blocking the protein-protein interaction. Optimization of the series, focusing on potency in human buffer and plasma clotlysis assays, permeability, and GABAa selectivity, led to the discovery of AZD6564 (19) displaying an in vitro human plasma clot lysis IC50 of 0.44 μM, no detectable activity against GABAa, and with DMPK properties leading to a predicted dose of 340 mg twice a day oral dosing in humans.

PubMed: 24900876
DOI: 10.1021/ML400526D

Experimental method

X-RAY DIFFRACTION (1.78 Å)