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Macrophage migration inhibitory factor (MIF) is an essential signaling cytokine with a key role in the immune system. Binding of MIF to its molecular targets such as, among others, the cluster of differentiation 74 (CD74) receptor plays a key role in inflammatory diseases and cancer. Therefore, the identification of MIF binding compounds gained importance in drug discovery. In this study, we aimed to discover novel MIF binding compounds by screening of a focused compound collection for inhibition of its tautomerase enzyme activity. Inspired by the known chromen-4-one inhibitor Orita-13, a focused collection of compounds with a chromene scaffold was screened for MIF binding. The library was synthesized using versatile cyanoacetamide chemistry to provide diversely substituted chromenes. The screening provided inhibitors with IC50's in the low micromolar range. Kinetic evaluation suggested that the inhibitors were reversible and did not bind in the binding pocket of the substrate. Thus, we discovered novel inhibitors of the MIF tautomerase activity, which may ultimately support the development of novel therapeutic agents against diseases in which MIF is involved.

Original publication

DOI

10.1016/j.bmc.2017.12.032

Type

Journal article

Journal

Bioorganic & medicinal chemistry

Publication Date

03/2018

Volume

26

Pages

999 - 1005

Addresses

Department of Chemical and Pharmaceutical Biology, University of Groningen, Groningen, The Netherlands; Faculty of Biotechnology, University of Surabaya, Jalan Raya Kalirungkut, Surabaya 60292, Indonesia.

Keywords

Humans, Benzopyrans, Intramolecular Oxidoreductases, Macrophage Migration-Inhibitory Factors, Crystallography, X-Ray, Inhibitory Concentration 50, Binding Sites, Molecular Conformation, Protein Binding, Structure-Activity Relationship, Kinetics, Molecular Dynamics Simulation