4-iodo-6-phenylpyrimidine and Lung-Neoplasms

The homologous cytokines macrophage migration inhibitory factor (MIF) and d-dopachrome tautomerase (d-DT or MIF2) play key roles in cancers. Molecules binding to the MIF tautomerase active site interfere with its biological activity. In contrast, the lack of potent MIF2 inhibitors hinders the exploration of MIF2 as a drug target. In this work, screening of a focused compound collection enabled the identification of a MIF2 tautomerase inhibitor R110. Subsequent optimization provided inhibitor

Topics: Antineoplastic Agents; Binding Sites; Carcinoma, Non-Small-Cell Lung; Cell Culture Techniques; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Drug Design; Extracellular Signal-Regulated MAP Kinases; Humans; Intramolecular Oxidoreductases; Kinetics; Lung Neoplasms; Macrophage Migration-Inhibitory Factors; Molecular Dynamics Simulation; Phosphorylation; Pyrimidinones; Structure-Activity Relationship

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.

Topics: Adenocarcinoma; Cell Growth Processes; Cell Line, Tumor; Cell Movement; Humans; Intramolecular Oxidoreductases; Isoxazoles; Lung Neoplasms; Macrophage Migration-Inhibitory Factors; Models, Molecular; Pyrimidines