Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti‐Proliferative Activity in Lung Cancer Cells

Xiao, Zhangping; Song, Shanshan; Chen, Deng; Merkerk, Ronald van; Wouden, Petra E van der; Cool, Robbert H.; Quax, Wim J.; Poelarends, Gerrit J.; Melgert, Barbro N.

doi:10.1002/anie.202101864

Cited by 28 publications

(16 citation statements)

References 65 publications

(130 reference statements)

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“… 27 , 28 Moreover, we developed a potent MIF-targeted proteolysis targeting chimera (PROTAC) to remove the MIF protein from its interaction network, which further expanded the toolbox to study MIF functions. 29 However, little is known about the effect of MIF2 inhibitors on cancer development due to a lack of potent MIF2 inhibitors and other effective molecular tools. 4-Iodo-6-phenylpyrimidine (4-IPP) is the firstly discovered MIF2 inhibitor, which covalently binds to proline-1 of MIF2 to interfere with its tautomerase enzyme activity and its biological function.…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…MIF is a cytokine closely associated with cancer and functions as a promoter in inflammation, and inhibition of MIF can suppress cancer cell proliferation [ 67 ]. Also, a study confirmed that proteolysis targeting chimera designed based on MIF tautomerase active site exhibited excellent anti-proliferative activity in lung cancer cells [ 68 ]. Moreover, exposure to SARS-CoV-2 spike protein combined with hypoxia enhanced MIF production [ 69 ].…”

Section: Discussionmentioning

confidence: 97%

Exploring the potential mechanism of emetine against coronavirus disease 2019 combined with lung adenocarcinoma: bioinformatics and molecular simulation analyses

et al. 2022

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Background Patients with lung adenocarcinoma (LUAD) may be more predisposed to coronavirus disease 2019 (COVID-19) and have a poorer prognosis. Currently, there is still a lack of effective anti-LUAD/COVID-19 drugs. Thus, this study aimed to screen for an effective anti-LUAD/COVID-19 drug and explore the potential mechanisms. Methods Firstly, we performed differentially expressed gene (DEG) analysis on LUAD transcriptome profiling data in The Cancer Genome Atlas (TCGA), where intersections with COVID-19-related genes were screened out. Then, we conducted Cox proportional hazards analyses on these LUAD/COVID-19 DEGs to construct a risk score. Next, LUAD/COVID-19 DEGs were uploaded on Connectivity Map to obtain drugs for anti-LUAD/COVID-19. Finally, we used network pharmacology, molecular docking, and molecular dynamics (MD) simulation to explore the drug’s therapeutic targets and potential mechanisms for anti-LUAD/COVID-19. Results We identified 230 LUAD/COVID-19 DEGs and constructed a risk score containing 7 genes (BTK, CCL20, FURIN, LDHA, TRPA1, ZIC5, and SDK1) that could classify LUAD patients into two risk groups. Then, we screened emetine as an effective drug for anti-LUAD/COVID-19. Network pharmacology analyses identified 6 potential targets (IL6, DPP4, MIF, PRF1, SERPING1, and SLC6A4) for emetine in anti-LUAD/COVID-19. Molecular docking and MD simulation analyses showed that emetine exhibited excellent binding capacities to DDP4 and the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Conclusions This study found that emetine may inhibit the entry and replication of SARS-CoV-2 and enhance tumor immunity by bounding to DDP4 and Mpro.

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“…c) Western blot assay of GPX4 level in HT‐1080 cells treated with different concentrations of ML162 and pomalidomide. d) Rescue from dGPX4‐mediated GPX4 degradation upon co‐treatment with CRBN‐inhibitor, pomalidomide, [16] and MG‐132. HT‐1080 cells were pre‐treated with indicated compounds for 12 h.…”

Section: Resultsmentioning

confidence: 99%

Intracellular Delivery of Glutathione Peroxidase Degrader Induces Ferroptosis In Vivo

et al. 2022

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Ferroptosis is a new form of regulated, nonapoptotic cell death driven by iron-dependent phospholipid peroxidation. Its therapeutic potential is however, greatly limited by the low efficiency of regulating cell ferroptosis in vivo. Herein, we report a PROTAC-based protein degrader that depletes endogenous glutathione peroxidase 4 (GPX4) and induces cancer cell ferroptosis. We demonstrate that a rationally designed GPX4 degrader, dGPX4, can deplete tumor cell GPX4 via proteasomal protein degradation, showing a five-fold enhancement of ferroptosis induction efficiency compared to that of GPX4 inhibition using ML162. Moreover, we show that the intracellular delivery of dGPX4 using biodegradable lipid nanoparticles (

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Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti‐Proliferative Activity in Lung Cancer Cells

Cited by 28 publications

References 65 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

Exploring the potential mechanism of emetine against coronavirus disease 2019 combined with lung adenocarcinoma: bioinformatics and molecular simulation analyses

Intracellular Delivery of Glutathione Peroxidase Degrader Induces Ferroptosis In Vivo

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