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Rational design and characterization of a DNA/HDAC dual-targeting inhibitor containing nitrogen mustard and 2-aminobenzamide moieties.

ABSTRACT: Histone deacetylases (HDACs) play a key role not only in gene expression but also in DNA repair. Herein, we report the rational design and characterization of a compound named chlordinaline containing nitrogen mustard and 2-aminobenzamide moieties as a DNA/HDAC dual-targeting inhibitor. Chlordinaline exhibited moderate total HDAC inhibitory activity. The HDAC isoform selectivity assay indicated that chlordinaline mostly inhibits HDAC3. Chlordinaline exhibited both DNA and HDAC inhibitory activities and showed potent antiproliferative activity against all the six test cancer cell lines with IC50 values of as low as 3.1-14.2 ?M, which is significantly more potent than reference drugs chlorambucil and tacedinaline. Chlordinaline could induce the apoptosis and G2/M phase cell cycle arrest of A375 cancer cells. This study demonstrates that combining nitrogen mustard and 2-aminobenzamide moieties into one molecule is an effective method to obtain DNA/HDAC dual-targeting inhibitors as potent antitumor agents. Chlordinaline as the first example of such DNA/HDAC dual-targeting inhibitors could be a promising candidate for cancer therapy and could also be a lead compound for further optimization.

SUBMITTER: Xie R

PROVIDER: S-EPMC6083786 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Rational design and characterization of a DNA/HDAC dual-targeting inhibitor containing nitrogen mustard and 2-aminobenzamide moieties.

Xie Rui R Tang Pingwah P Yuan Qipeng Q

MedChemComm 20171227 2

Histone deacetylases (HDACs) play a key role not only in gene expression but also in DNA repair. Herein, we report the rational design and characterization of a compound named chlordinaline containing nitrogen mustard and 2-aminobenzamide moieties as a DNA/HDAC dual-targeting inhibitor. Chlordinaline exhibited moderate total HDAC inhibitory activity. The HDAC isoform selectivity assay indicated that chlordinaline mostly inhibits HDAC3. Chlordinaline exhibited both DNA and HDAC inhibitory activit ...[more]

PMID: 30108928

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Project description:The genetic defect in Friedreich's ataxia (FRDA) is the hyperexpansion of a GAA•TTC triplet in the first intron of the FXN gene, encoding the essential mitochondrial protein frataxin. Histone post-translational modifications near the expanded repeats are consistent with heterochromatin formation and consequent FXN gene silencing. Using a newly developed human neuronal cell model, derived from patient-induced pluripotent stem cells, we find that 2-aminobenzamide histone deacetylase (HDAC) inhibitors increase FXN mRNA levels and frataxin protein in FRDA neuronal cells. However, only compounds targeting the class I HDACs 1 and 3 are active in increasing FXN mRNA in these cells. Structural analogs of the active HDAC inhibitors that selectively target either HDAC1 or HDAC3 do not show similar increases in FXN mRNA levels. To understand the mechanism of action of these compounds, we probed the kinetic properties of the active and inactive inhibitors, and found that only compounds that target HDACs 1 and 3 exhibited a slow-on/slow-off mechanism of action for the HDAC enzymes. HDAC1- and HDAC3-selective compounds did not show this activity. Using siRNA methods in the FRDA neuronal cells, we show increases in FXN mRNA upon silencing of either HDACs 1 or 3, suggesting the possibility that inhibition of each of these class I HDACs is necessary for activation of FXN mRNA synthesis, as there appears to be redundancy in the silencing mechanism caused by the GAA•TTC repeats. Moreover, inhibitors must have a long residence time on their target enzymes for this activity. By interrogating microarray data from neuronal cells treated with inhibitors of different specificity, we selected two genes encoding histone macroH2A (H2AFY2) and Polycomb group ring finger 2 (PCGF2) that were specifically down-regulated by the inhibitors targeting HDACs1 and 3 versus the more selective inhibitors for further investigation. Both genes are involved in transcriptional repression and we speculate their involvement in FXN gene silencing. Our results shed light on the mechanism whereby HDAC inhibitors increase FXN mRNA levels in FRDA neuronal cells.

Dataset Information

Rational design and characterization of a DNA/HDAC dual-targeting inhibitor containing nitrogen mustard and 2-aminobenzamide moieties.

Publications

Rational design and characterization of a DNA/HDAC dual-targeting inhibitor containing nitrogen mustard and 2-aminobenzamide moieties.

Similar Datasets

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