2 research outputs found
Structure-Based Design and Biological Characterization of Selective Histone Deacetylase 8 (HDAC8) Inhibitors with Anti-Neuroblastoma Activity
Histone deacetylases (HDACs) are
important modulators of epigenetic
gene regulation and additionally control the activity of non-histone
protein substrates. While for HDACs 1–3 and 6 many potent selective
inhibitors have been obtained, for other subtypes much less is known
on selective inhibitors and the consequences of their inhibition.
The present report describes the development of substituted benzhydroxamic
acids as potent and selective HDAC8 inhibitors. Docking studies using
available crystal structures have been used for structure-based optimization
of this series of compounds. Within this study, we have investigated
the role of HDAC8 in the proliferation of cancer cells and optimized
hits for potency and selectivity, both in vitro and in cell culture.
The combination of structure-based design, synthesis, and in vitro
screening to cellular testing resulted in potent and selective HDAC8
inhibitors that showed anti-neuroblastoma activity in cellular testing
Harnessing the Role of HDAC6 in Idiopathic Pulmonary Fibrosis: Design, Synthesis, Structural Analysis, and Biological Evaluation of Potent Inhibitors.
Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by a progressive-fibrosing phenotype. IPF has been associated with aberrant HDAC activities confirmed by our immunohistochemistry studies on HDAC6 overexpression in IPF lung tissues. We herein developed a series of novel hHDAC6 inhibitors, having low inhibitory potency over hHDAC1 and hHDAC8, as potential pharmacological tools for IPF treatment. Their inhibitory potency was combined with low in vitro and in vivo toxicity. Structural analysis of 6h and structure–activity relationship studies contributed to the optimization of the binding mode of the new molecules. The best-performing analogues were tested for their efficacy in inhibiting fibrotic sphere formation and cell viability, proving their capability in reverting the IPF phenotype. The efficacy of analogue 6h was also determined in a validated human lung model of TGF-β1-dependent fibrogenesis. The results highlighted in this manuscript may pave the way for the identification of first-in-class molecules for the treatment of IPF