3B9S

Macrophage Migration Inhibitory Factor (MIF) complexed with Inhibitor, 4-IPP.

Summary for 3B9S

• Entry DOI: 10.2210/pdb3b9s/pdb
• Related: 1MIF
• Descriptor: Macrophage Migration Inhibitory Factor, GLYCEROL, 4-phenylpyrimidine, ... (5 entities in total)
• Functional Keywords: macrophage migration inhibitory factor, cytokine
• Biological source: Homo sapiens
• Cellular location: Secreted : P14174
• Total number of polymer chains: 3
• Total formula weight: 38194.25

Authors

Zierow, S.,Crichlow, G.,Lolis, E. (deposition date: 2007-11-06, release date: 2008-09-23, Last modification date: 2024-10-30)

Primary citation

Winner, M.,Meier, J.,Zierow, S.,Rendon, B.E.,Crichlow, G.V.,Riggs, R.,Bucala, R.,Leng, L.,Smith, N.,Lolis, E.,Trent, J.O.,Mitchell, R.A.
A novel, macrophage migration inhibitory factor suicide substrate inhibits motility and growth of lung cancer cells.
Cancer Res., 68:7253-7257, 2008

PubMed Abstract: Although chemokine and growth factor receptors are attractive and popular targets for cancer therapeutic intervention, structure-based targeting of the ligands themselves is generally not considered practical. New evidence indicates that a notable exception to this is macrophage migration inhibitory factor (MIF). MIF, an autocrine- and paracrine-acting cytokine/growth factor, plays a pivotal role in both the initiation and maintenance of neoplastic diseases. MIF possesses a nonphysiologic enzymatic activity that is evolutionarily well-conserved. Although small molecule antagonists of MIFs enzymatic active site have been reported to inhibit biological activities of MIF, universally high IC(50)s have limited their clinical appeal. Using a computational virtual screening strategy, we have identified a unique small molecule inhibitor that serves as a suicide substrate for MIF, resulting in the covalent modification of the catalytically active NH(2)-terminal proline. Our studies further reveal that this compound, 4-iodo-6-phenylpyrimidine (4-IPP), is approximately 5x to 10x times more potent in blocking MIF-dependent catalysis and lung adenocarcinoma cell migration and anchorage-independent growth than the prototypical MIF inhibitor, ISO-1. Finally, using an in silico combinatorial optimization strategy, we have identified four unique congeners of 4-IPP that exhibit MIF inhibitory activity at concentrations 10x to 20x lower than that of parental 4-IPP.

PubMed: 18794110
DOI: 10.1158/0008-5472.CAN-07-6227

Experimental method

X-RAY DIFFRACTION (1.8 Å)