MIF is a cytokine that plays a key role in innate and adaptive immune responses. Its activity has been associated with the development of multiple inflammatory diseases and cancer. MIF exerts its biological functions through the interaction with its cellular receptors such as CD74. Hence, MIF-CD74 binding is considered to be a promising target in the development of therapeutics for MIF cytokine-related diseases. We successfully improve the production of the purified CD74 protein in bacteria in order to provide a suitable MIF-CD74 binding assay. Furthermore, we have developed novel types of MIF inhibitors. The first type was identified from a collection of diversely-substituted compounds with a chromene scaffold. Screening of this compound collection yielded several hit compounds with IC50’s in the low micromolar range. Preincubation and dilution assays indicated that the inhibitors bind to MIF reversibly. Enzyme kinetic analysis of the most potent inhibitor showed that the inhibitor does not bind in direct competition with the substrate 4-HPP. Further characterization of the newly identified inhibitors in MIF-CD74 interaction assays is needed, as well as further characterizations in MIF cytokine-activity assays and in relevant disease models. For the second type of MIF inhibitors we employed structure-based design starting from known inhibitors with a triazole-phenol scaffold. The observed structure-activity relationships suggest that the triazole-phenol is a promising scaffold for systematic cycles of design and synthesis to further elucidate the structure activity relationships in MIF binding.
|Kwalificatie||Doctor of Philosophy|
|Datum van toekenning||25-jan-2019|
|Plaats van publicatie||[Groningen]|
|Status||Published - 2019|