Identification and Characterization of Novel Classes of Macrophage Migration Inhibitory Factor (MIF) Inhibitors with Distinct Mechanisms of Action

Article (PDF Available)inJournal of Biological Chemistry 285(34):26581-98 · August 2010with27 Reads
DOI: 10.1074/jbc.M110.113951 · Source: PubMed
Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, is considered an attractive therapeutic target in multiple inflammatory and autoimmune disorders. In addition to its known biologic activities, MIF can also function as a tautomerase. Several small molecules have been reported to be effective inhibitors of MIF tautomerase activity in vitro. Herein we employed a robust activity-based assay to identify different classes of novel inhibitors of the catalytic and biological activities of MIF. Several novel chemical classes of inhibitors of the catalytic activity of MIF with IC(50) values in the range of 0.2-15.5 microm were identified and validated. The interaction site and mechanism of action of these inhibitors were defined using structure-activity studies and a battery of biochemical and biophysical methods. MIF inhibitors emerging from these studies could be divided into three categories based on their mechanism of action: 1) molecules that covalently modify the catalytic site at the N-terminal proline residue, Pro(1); 2) a novel class of catalytic site inhibitors; and finally 3) molecules that disrupt the trimeric structure of MIF. Importantly, all inhibitors demonstrated total inhibition of MIF-mediated glucocorticoid overriding and AKT phosphorylation, whereas ebselen, a trimer-disrupting inhibitor, additionally acted as a potent hyperagonist in MIF-mediated chemotactic migration. The identification of biologically active compounds with known toxicity, pharmacokinetic properties, and biological activities in vivo should accelerate the development of clinically relevant MIF inhibitors. Furthermore, the diversity of chemical structures and mechanisms of action of our inhibitors makes them ideal mechanistic probes for elucidating the structure-function relationships of MIF and to further determine the role of the oligomerization state and catalytic activity of MIF in regulating the function(s) of MIF in health and disease.
    • "The platform does not privilege any particular biological discipline or therapeutic area and performs screens in (but *Address correspondence to this author at the Biomolecular Screening Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), Station 15, Lausanne 1015, Switzerland; Tel: +41 21 693 96 66; E-mail: not limited to) the areas of cancer research [2] [3], neurobiology [4] [5], and metabolic and infectious diseases [6] for researchers interested in drug discovery, chemical biology and systems biology. This 'generic' and flexible concept was extended to the type of screening assays and the nature of compounds to be tested. "
    [Show abstract] [Hide abstract] ABSTRACT: The Biomolecular Screening Facility (BSF) is a multidisciplinary laboratory created in 2006 at the École Polytechnique Fédérale de Lausanne (EPFL) to perform medium and high throughput screening in life sciences-related projects. The BSF was conceived and developed to meet the needs of a wide range of researchers, without privileging a particular biological discipline or therapeutic area. The facility has the necessary infrastructure, multidisciplinary expertise and flexibility to perform large screening programs using small interfering RNAs (siRNAs) and chemical collections in the areas of chemical biology, systems biology and drug discovery. In the framework of the National Centres of Competence in Research (NCCR) Chemical Biology, the BSF is hosting 'ACCESS', the Academic Chemical Screening Platform of Switzerland that provides the scientific community with chemical diversity, screening facilities and know-how in chemical genetics. In addition, the BSF started its own applied research axes that are driven by innovation in thematic areas related to preclinical drug discovery and discovery of bioactive probes.
    Full-text · Article · Mar 2014
    • "In conclusion, multiple animal and human studies support MIF's pro-atherosclerotic and pro-inflammatory role, and reveal MIF as an interesting target for drug development. The list of MIF inhibitors is steadily growing and includes small molecular weight or peptide drugs targeting mostly MIF's catalytic pocket or MIF trimerization (Garai and Lorand, 2009; Ouertatani-Sakouhi et al., 2010 ). An interesting therapeutic strategy would be to interfere with the CLF functions of MIF by blocking the interaction of MIF with its receptors. "
    [Show abstract] [Hide abstract] ABSTRACT: Macrophage migration inhibitory factor (MIF) has been defined as an important chemokine-like function (CLF) chemokine with an essential role in monocyte recruitment and arrest. Adhesion of monocytes to the vessel wall and their transendothelial migration are critical in atherogenesis and many other inflammatory diseases. Chemokines carefully control all steps of the monocyte recruitment process. Those chemokines specialized in controlling arrest are typically immobilized on the endothelial surface, mediating the arrest of rolling monocytes by chemokine receptor-triggered pathways. The chemokine receptor CXCR2 functions as an important arrest receptor on monocytes. An arrest function has been revealed for the bona fide CXCR2 ligands CXCL1 and CXCL8, but genetic studies also suggested that additional arrest chemokines are likely to be involved in atherogenic leukocyte recruitment. While CXCR2 is known to interact with numerous CXC chemokine ligands, the CLF-chemokine MIF, which structurally does not belong to the CXC chemokine sub-family, was surprisingly identified as a non-cognate ligand of CXCR2, responsible for critical arrest functions during the atherogenic process. MIF was originally identified as macrophage migration inhibitory factor, but is now known as a potent inflammatory cytokine with chemokine-like functions including chemotaxis and leukocyte arrest. This review will cover the mechanisms underlying these functions, including MIF’s effects on LFA1 integrin activity and signal transduction, and will discuss the structural similarities between MIF and the bona fide CXCR2 ligand CXCL8 while emphasizing the structural differences. As MIF also interacts with CXCR4, a chemokine receptor implicated in CXCL12-elicited lymphocyte arrest, the arrest potential of the MIF/CXCR4 axis will also be scrutinized as well as the recently identified role of pericyte MIF in attracting leukocytes exiting through venules as part of the pericyte 'motility instruction program'.
    Full-text · Article · May 2013
    • "A total of 79 compounds were used in this study (1–79, seeTable A under supplementary material)34353660,61] . Seven training subsets were selected from the collection. "
    [Show abstract] [Hide abstract] ABSTRACT: Recent research suggested the involvement of migration inhibitor factor (MIF) in cancer and inflammatory diseases, which prompted several attempts to develop new MIF inhibitors. Accordingly, we investigated the pharmacophoric space of 79 MIF inhibitors using seven diverse subsets of inhibitors to identify plausible binding hypotheses (pharmacophores). Subsequently, we implemented genetic algorithm and multiple linear regression analysis to select optimal combination of pharmacophores and physicochemical descriptors capable of explaining bioactivity variation within the training compounds (QSAR model, r63=0.62, F=42.8, rLOO(2)=0.721,rPRESS(2) against 16 external test inhibitors=0.58). Two orthogonal pharmacophores appeared in the optimal QSAR model suggestive of at least two binding modes available to ligands inside MIF binding pocket. Subsequent validation using receiver operating characteristic (ROC) curves analysis established the validity of these two pharmacophores. We employed these pharmacophoric models and associated QSAR equation to screen the National Cancer Institute (NCI) list of compounds. Eight compounds gave >50% inhibition at 100μM. Two molecules illustrated >75% inhibition at 10μM.
    Full-text · Article · Mar 2013
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