| 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
|
| リソース情報 |
| ヒト・動物細胞 |
HE19(RCB2239) |
