論文 - 詳細
| RRC ID | 18528 |
|---|---|
| 著者 | Upadhyay AK, Rotili D, Han JW, Hu R, Chang Y, Labella D, Zhang X, Yoon YS, Mai A, Cheng X. |
| タイトル | An analog of BIX-01294 selectively inhibits a family of histone H3 lysine 9 Jumonji demethylases. |
| ジャーナル | J Mol Biol |
| Abstract |
BIX-01294 and its analogs were originally identified and subsequently designed as potent inhibitors against histone H3 lysine 9 (H3K9) methyltransferases G9a and G9a-like protein. Here, we show that BIX-01294 and its analog E67 can also inhibit H3K9 Jumonji demethylase KIAA1718 with half-maximal inhibitory concentrations in low micromolar range. Crystallographic analysis of KIAA1718 Jumonji domain in complex with E67 indicated that the benzylated six-membered piperidine ring was disordered and exposed to solvent. Removing the moiety (generating compound E67-2) has no effect on the potency against KIAA1718 but, unexpectedly, lost inhibition against G9a-like protein by a factor of 1500. Furthermore, E67 and E67-2 have no effect on the activity against histone H3 lysine 4 (H3K4) demethylase JARID1C. Thus, our study provides a new avenue for designing and improving the potency and selectivity of inhibitors against H3K9 Jumonji demethylases over H3K9 methyltransferases and H3K4 demethylases. |
| 巻・号 | 416(3) |
| ページ | 319-27 |
| 公開日 | 2012-2-24 |
| DOI | 10.1016/j.jmb.2011.12.036 |
| PII | S0022-2836(11)01365-9 |
| PMID | 22227394 |
| PMC | PMC3280428 |
| MeSH | Animals Azepines / pharmacology* Cells, Cultured Crystallography, X-Ray Enzyme Inhibitors / chemistry Enzyme Inhibitors / pharmacology* Fibroblasts / drug effects Fibroblasts / enzymology Histone Methyltransferases Histone-Lysine N-Methyltransferase / antagonists & inhibitors Histones / metabolism Humans Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors* Jumonji Domain-Containing Histone Demethylases / chemistry Mice Protein Structure, Tertiary Quinazolines / pharmacology* |
| IF | 4.76 |
| 引用数 | 39 |
| WOS 分野 | BIOCHEMISTRY & MOLECULAR BIOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 2 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | HE19(RCB2239) |