Macrophage Migration Inhibitory Factor Acts as the Potential Target of a Newly Synthesized Compound, 1-(9'-methyl-3'-carbazole)-3, 4-dihydro-β-carboline

Sci Rep. 2019 Feb 14;9(1):2147. doi: 10.1038/s41598-019-38590-y.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Biomarkers, Tumor
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Carbazoles / chemistry
  • Carbazoles / pharmacology*
  • Carbolines / chemistry
  • Carbolines / pharmacology*
  • Cell Cycle
  • Cell Proliferation
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Intramolecular Oxidoreductases / antagonists & inhibitors*
  • Intramolecular Oxidoreductases / metabolism
  • Macrophage Migration-Inhibitory Factors / antagonists & inhibitors*
  • Macrophage Migration-Inhibitory Factors / metabolism
  • Phosphorylation
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Carbazoles
  • Carbolines
  • Macrophage Migration-Inhibitory Factors
  • Intramolecular Oxidoreductases
  • MIF protein, human