Discovery of potent HDAC inhibitors based on chlamydocin with inhibitory effects on cell migration.

Shimiao Wang, Xiaohui Li, Yingdong Wei, Zhilong Xiu, Norikazu Nishino

ChemMedChem 2014 Mar

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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. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Citation

Shimiao Wang, Xiaohui Li, Yingdong Wei, Zhilong Xiu, Norikazu Nishino. Discovery of potent HDAC inhibitors based on chlamydocin with inhibitory effects on cell migration. ChemMedChem. 2014 Mar;9(3):627-37