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An Analog of BIX-01294 Selectively Inhibits a Family of Histone H3 Lysine 9 Jumonji Demethylases

Authors
 Anup K. Upadhyay  ;  Dante Rotili  ;  Ji Woong Han  ;  Ruogu Hu  ;  Yanqi Chang  ;  Donatella Labella  ;  Xing Zhang  ;  Young-sup Yoon  ;  Antonello Mai  ;  Xiaodong Cheng 
Citation
 JOURNAL OF MOLECULAR BIOLOGY, Vol.416(3) : 319-327, 2012 
Journal Title
 JOURNAL OF MOLECULAR BIOLOGY 
ISSN
 0022-2836 
Issue Date
2012
MeSH
Animals ; Azepines/pharmacology* ; Cells, Cultured ; Crystallography, X-Ray ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology* ; Fibroblasts/drug effects ; Fibroblasts/enzymology ; 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*
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.
Files in This Item:
T201206317.pdf Download
DOI
10.1016/j.jmb.2011.12.036
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Yoon, Young Sup(윤영섭)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/158313
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