Macrophage Migration Inhibitory Factor Acts as the Potential Target of a Newly Synthesized Compound, 1-(9′-methyl-3′-carbazole)-3, 4-dihydro-β-carboline
Journal
Scientific Reports
Journal Volume
9
Journal Issue
1
Date Issued
2019
Author(s)
Ko P.-H
Shen Y.-C
Murugan K
Huang C.-W
Sivakumar G
Pal P
Liao C.-C
Luo K.-S
Abstract
For a newly synthesized compound, identifying its target protein is a slow but pivotal step toward understand its pharmacologic mechanism. In this study, we systemically synthesized novel manzamine derivatives and chose 1-(9′-methyl-3′-carbazole)-3, 4-dihydro-β-carboline (MCDC) as an example to identify its target protein and function. MCDC had potent toxicity against several cancer cells. To identify its target protein, we first used a docking screen to predict macrophage migration inhibitory factor (MIF) as the potential target. Biochemical experiments, including mutation analysis and hydrogen-deuterium exchange assays, validated the binding of MCDC to MIF. Furthermore, MCDC was shown by microarrays to interfere with the cell cycle of breast cancer MCF7 cells. The activated signaling pathways included AKT phosphorylation and S phase-related proteins. Our results showed MIF as a potential direct target of a newly synthesized manzamine derivative, MCDC, and its pharmacologic mechanisms. © 2019, The Author(s).
Other Subjects
antineoplastic agent; carbazole derivative; carboline derivative; isomerase; macrophage migration inhibition factor; MIF protein, human; tumor marker; apoptosis; breast tumor; cell cycle; cell proliferation; chemistry; drug effect; female; gene expression profiling; gene expression regulation; human; metabolism; pathology; phosphorylation; tumor cell culture; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Breast Neoplasms; Carbazoles; Carbolines; Cell Cycle; Cell Proliferation; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Intramolecular Oxidoreductases; Macrophage Migration-Inhibitory Factors; Phosphorylation; Tumor Cells, Cultured
Type
journal article