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

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.