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.