Structure-activity relationships for binding of 4-substituted triazole-phenols to macrophage migration inhibitory factor (MIF)

Xiao, Zhangping; Fokkens, Marieke; Chen, Deng; Kok, Tjie; Proietti, Giordano; Merkerk, Ronald van; Poelarends, Gerrit J.

doi:10.1016/j.ejmech.2019.111849

Cited by 13 publications

(37 citation statements)

References 44 publications

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“…In this assay format, a MIF2 solution in assay buffer was mixed with the compound stock solution and an aqueous EDTA solution followed by 10 min preincubation. 35 The assay was started by adding a PP solution to the inhibitor–enzyme mixture. In the final reaction mixture, there were 50 nM MIF2, 0.5 mM PP, 2.5% (v/v) dimethyl sulfoxide (DMSO), and variable concentrations of the inhibitor.…”

Section: Resultsmentioning

confidence: 99%

“… 36 Similar to MIF, we observed that Cu 2+ ions interfere with this MIF2 tautomerase activity assay and that including EDTA in the assay buffer prevents this ( Figure 3 D). 35 …”

Section: Resultsmentioning

confidence: 99%

“…The MIF tautomerase activity and enzyme kinetics were measured by a previously described protocol. 35 The methods to study MIF2 enzyme activity were adapted from protocols to study MIF. Briefly, 10 μL of EDTA (20 mM) solution in demiwater was added into 180 μL of MIF2 solution (100 nM) in boric acid buffer (435 mM, pH 6.2), followed by the addition of 10 μL of the desired compound in DMSO or vehicle.…”

Section: Methodsmentioning

confidence: 99%

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Thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione Derivative Inhibits d-Dopachrome Tautomerase Activity and Suppresses the Proliferation of Non-Small Cell Lung Cancer Cells

et al. 2022

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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 5d with an IC 50 of 1.0 μM for MIF2 tautomerase activity and a high selectivity over MIF. 5d suppressed the proliferation of non-small cell lung cancer cells in two-dimensional (2D) and three-dimensional (3D) cell cultures, which can be explained by the induction of cell cycle arrest via deactivation of the mitogen-activated protein kinase (MAPK) pathway. Thus, we discovered and characterized MIF2 inhibitors ( 5d ) with improved antiproliferative activity in cellular models systems, which indicates the potential of targeting MIF2 in cancer treatment.

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Section: Resultsmentioning

confidence: 99%

“… 36 Similar to MIF, we observed that Cu 2+ ions interfere with this MIF2 tautomerase activity assay and that including EDTA in the assay buffer prevents this ( Figure 3 D). 35 …”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione Derivative Inhibits d-Dopachrome Tautomerase Activity and Suppresses the Proliferation of Non-Small Cell Lung Cancer Cells

et al. 2022

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“…The linear regression parameters were determined to calculate IC 50 using GraphPad Prism. The IC 50 values were transformed to K i values using the Cheng–Prusoff equation: K i = IC 50 /(1 + [S]/ K m ), in which [S] is the substrate concentration (0.5 mM) and K m is the Michaelis–Menten constant (1.0 mM) …”

Section: Resultsmentioning

confidence: 99%

7-Hydroxycoumarins Are Affinity-Based Fluorescent Probes for Competitive Binding Studies of Macrophage Migration Inhibitory Factor

et al. 2020

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Macrophage migration inhibitory factor (MIF) is a cytokine with key roles in inflammation and cancer, which qualifies it as a potential drug target. Apart from its cytokine activity, MIF also harbors enzyme activity for keto–enol tautomerization. MIF enzymatic activity has been used for identification of MIF binding molecules that also interfere with its biological activity. However, MIF tautomerase activity assays are troubled by irregularities, thus creating a need for alternative methods. In this study, we identified a 7-hydroxycoumarin fluorophore with high affinity for the MIF tautomerase active site ( K i = 18 ± 1 nM) that binds with concomitant quenching of its fluorescence. This property enabled development of a novel competition-based assay format to quantify MIF binding. We also demonstrated that the 7-hydroxycoumarin fluorophore interfered with the MIF–CD74 interaction and inhibited proliferation of A549 cells. Thus, we provide a high-affinity MIF binder as a novel tool to advance MIF-oriented research.

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“…ISO-1 is one of the most used and studied small molecules targeting MIF and was found to have anti-inflammatory properties attenuating acute kidney and lung injury in many models [ 29 , 135 ]. In addition, many research groups have discovered several more potent tautomerase inhibitors such as Jorgensen-3b, NVS 2, and Dekker 7, that exhibit nanomolar-level binding affinity for MIF [ 136 – 138 ].…”

Section: Mif-targeting Therapeuticsmentioning

confidence: 99%

Macrophage migration inhibitory factor family proteins are multitasking cytokines in tissue injury

Song

Xiao

Poelarends

et al. 2022

Cell. Mol. Life Sci.

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The family of macrophage migration inhibitory factor (MIF) proteins in humans consist of MIF, its functional homolog D-dopachrome tautomerase (D-DT, also known as MIF-2) and the relatively unknown protein named DDT-like (DDTL). MIF is a pleiotropic cytokine with multiple properties in tissue homeostasis and pathology. MIF was initially found to associate with inflammatory responses and therefore established a reputation as a pro-inflammatory cytokine. However, increasing evidence demonstrates that MIF influences many different intra- and extracellular molecular processes important for the maintenance of cellular homeostasis, such as promotion of cellular survival, antioxidant signaling, and wound repair. In contrast, studies on D-DT are scarce and on DDTL almost nonexistent and their functions remain to be further investigated as it is yet unclear how similar they are compared to MIF. Importantly, the many and sometimes opposing functions of MIF suggest that targeting MIF therapeutically should be considered carefully, taking into account timing and severity of tissue injury. In this review, we focus on the latest discoveries regarding the role of MIF family members in tissue injury, inflammation and repair, and highlight the possibilities of interventions with therapeutics targeting or mimicking MIF family proteins.

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Structure-activity relationships for binding of 4-substituted triazole-phenols to macrophage migration inhibitory factor (MIF)

Cited by 13 publications

References 44 publications

Thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione Derivative Inhibits d-Dopachrome Tautomerase Activity and Suppresses the Proliferation of Non-Small Cell Lung Cancer Cells

Thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione Derivative Inhibits d-Dopachrome Tautomerase Activity and Suppresses the Proliferation of Non-Small Cell Lung Cancer Cells

7-Hydroxycoumarins Are Affinity-Based Fluorescent Probes for Competitive Binding Studies of Macrophage Migration Inhibitory Factor

Macrophage migration inhibitory factor family proteins are multitasking cytokines in tissue injury

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