Novel Allosteric Inhibitors of Deoxyhypusine Synthase against Malignant Melanoma: Design, Synthesis, and Biological Evaluation

J Med Chem. 2021 Sep 23;64(18):13356-13372. doi: 10.1021/acs.jmedchem.1c00582. Epub 2021 Sep 2.

Abstract

Based on the novel allosteric site of deoxyhypusine synthase (DHPS), two series of 30 novel 5-(2-methoxyphenoxy)-2-phenylpyrimidin-4-amine derivatives as DHPS inhibitors were designed and synthesized. Among them, compound 8m, with the best DHPS inhibitory potency (IC50 = 0.014 μM), exhibited excellent inhibition against melanoma cells, which was superior to that of GC7. Besides, molecular docking and molecular dynamics (MD) simulations further proved that compound 8m was tightly bound to the allosteric site of DHPS. Flow cytometric analysis and enzyme-linked immunosorbent assay (ELISA) showed that compound 8m could inhibit the intracellular reactive oxygen species (ROS) level. Furthermore, by western blot analysis, compound 8m effectively activated caspase 3 and decreased the expressions of GP-100, tyrosinase, eIF5A2, MMP2, and MMP9. Moreover, both Transwell analysis and wound healing analysis showed that compound 8m could inhibit the invasion and migration of melanoma cells. In the in vivo study, the tumor xenograft model showed that compound 8m effectively inhibited melanoma development with low toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Site
  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / therapeutic use*
  • Female
  • Humans
  • Male
  • Melanoma / drug therapy*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Oxidoreductases Acting on CH-NH Group Donors / antagonists & inhibitors*
  • Oxidoreductases Acting on CH-NH Group Donors / chemistry
  • Oxidoreductases Acting on CH-NH Group Donors / metabolism
  • Protein Binding
  • Pyrimidines / chemical synthesis
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Pyrimidines
  • Oxidoreductases Acting on CH-NH Group Donors
  • deoxyhypusine synthase