Design, synthesis, enzyme-inhibitory activity, and effect on human cancer cells of a novel series of jumonji domain-containing protein 2 histone demethylase inhibitors.

  title={Design, synthesis, enzyme-inhibitory activity, and effect on human cancer cells of a novel series of jumonji domain-containing protein 2 histone demethylase inhibitors.},
  author={Shohei Hamada and Takayoshi Suzuki and Koshiki Mino and Koichi Koseki and Felix Oehme and Ingo Flamme and Hiroki Ozasa and Yukihiro Itoh and Daisuke Ogasawara and Haruka Komaarashi and Aiko Kato and Hiroki Tsumoto and Hidehiko Nakagawa and Makoto Hasegawa and Ryuzo Sasaki and Tamio Mizukami and Naoki Miyata},
  journal={Journal of medicinal chemistry},
  volume={53 15},
Selective inhibitors of Jumonji domain-containing protein (JMJD) histone demethylases are candidate anticancer agents as well as potential tools for elucidating the biological functions of JMJDs. On the basis of the crystal structure of JMJD2A and a homology model of JMJD2C, we designed and prepared a series of hydroxamate analogues bearing a tertiary amine. Enzyme assays using JMJD2C, JMJD2A, and prolyl hydroxylases revealed that hydroxamate analogue 8 is a potent and selective JMJD2 inhibitor… Expand
Novel 5-carboxy-8-HQ based histone demethylase JMJD2A inhibitors: introduction of an additional carboxyl group at the C-2 position of quinoline.
The data recognized that compound 6p could be considered as a starting point for development of new JmjC inhibitors and displayed good aqueous solubility and better permeability than 5-carboxy-8-HQ. Expand
Substituted 2-(2-aminopyrimidin-4-yl)pyridine-4-carboxylates as potent inhibitors of JumonjiC domain-containing histone demethylases.
Virtual screening and rational structural optimization led to a novel scaffold for highly potent and selective JMJD2A inhibitors. Expand
Identification of Jumonji AT-Rich Interactive Domain 1A Inhibitors and Their Effect on Cancer Cells.
Compound 6j, which selectively inhibits JARID1A over three other JHDM family members, and compound 7j synergistically enhanced A549 human lung cancer cell growth inhibition induced by vorinostat, a histone deacetylase inhibitor support the idea that JARIDs1A inhibitors have potential as anticancer agents. Expand
An analog of BIX-01294 selectively inhibits a family of histone H3 lysine 9 Jumonji demethylases.
It is shown that BIX-01294 and its analog E67 can also inhibit H3K9 Jumonji demethylase KIAA1718 with half-maximal inhibitory concentrations in low micromolar range. Expand
Screening of inhibitors against histone demethylation jumonji domain-containing protein 3 by capillary electrophoresis.
The merit of the capillary electrophoresis method is proved by discovering two new JMJD3 inhibitors: salvianic acid A and puerarin 6''-O-xyloside. Expand
Synthesis and Biological Evaluation of Tripartin, a Putative KDM4 Natural Product Inhibitor, and 1‐Dichloromethylinden‐1‐ol Analogues
Although the precise cellular mode of action of tripartin is unclear, the evidence suggests that it may affect histone methylation status via a mechanism other than direct inhibition of the KDM4 histone demethylases. Expand
Design and discovery of new pyrimidine coupled nitrogen aromatic rings as chelating groups of JMJD3 inhibitors.
The current study not only discovered alternative potent JMJD3 inhibitors, but also can benefit other researchers to design new series of Jumonji demethylase inhibitors based on the identified chelating groups. Expand
Linking of 2-oxoglutarate and substrate binding sites enables potent and highly selective inhibition of JmjC histone demethylases.
It is reported that a strategy involving binding to both the 2OG and substrate binding sites leads to selective and potent inhibitors of the JMJD2 subfamily, the largest family of demethylases in the world. Expand
Identification of novel lysine demethylase 5-selective inhibitors by inhibitor-based fragment merging strategy.
Several compounds are designed by strategically merging two fragments for competitive inhibition with α-ketoglutarate and for KDM5-selective inhibition, which should provide a basis for the development of cell-active K DM5 inhibitors and highlight the validity of the inhibitor-based fragment merging strategy. Expand
Pro-growth role of the JMJD2C histone demethylase in HCT-116 colon cancer cells and identification of curcuminoids as JMJD2 inhibitors.
It is highlighted that overexpression of JMJD2C confers a pro-growth effect on colon cancer cells and, therefore, its inhibition by curcuminoids or other small molecules could be beneficial as an adjuvant therapy for colon cancer patients. Expand