Discovery of Potent HDAC Inhibitors Based on Chlamydocin with Inhibitory Effects on Cell Migration

The histone deacetylase (HDAC) family is a promising drug target class owing to the importance of these enzymes in a variety of cellular processes. Docking studies were conducted to identify novel HDAC inhibitors. Subtle modifications in the recognition domain were introduced into a series of chlamydocin analogues, and the resulting scaffolds were combined with various zinc binding domains. Remarkably, cyclo(L‐Asu(NHOH)‐L‐A3mc6c‐L‐Phe‐D‐Pro, compound 1 b), with a methyl group at positions 3 or 5 on the aliphatic ring, exhibited better antiproliferative effects than trichostatin A (TSA) against MCF‐7 and K562 cell lines. In addition to cell‐cycle arrest and apoptosis, cell migration inhibition was observed in cells treated with compound 1 b. Subsequent western blot analysis revealed that the balance between matrix metalloproteinase 2 (MMP2) and tissue inhibitors of metalloproteinase 1 (TIMP1) determines the degree of metalloproteinase activity in MCF‐7 cells, thereby regulating cell migration. The improved inhibitory activity imparted by altering the hydrophobic substitution pattern at the bulky cap group is a valuable approach in the development of novel HDAC inhibitors. Keeping cells in their place: Inhibition of cell migration by improved HDAC inhibitory activity was realized by the design and synthesis of highly effective HDAC inhibitors. The interactions between target compounds and HDAC4 were predicted by docking analyses. Cell migration was completely inhibited after treatment with compound 1 b.