An analog of BIX-01294 selectively inhibits a family of histone H3 lysine 9 Jumonji demethylases.
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.
Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322, USA.
Anup K
AK
Upadhyay
Dante
D
Rotili
Ji Woong
JW
Han
Ruogu
R
Hu
Yanqi
Y
Chang
Donatella
D
Labella
Xing
X
Zhang
Young-Sup
YS
Yoon
Antonello
A
Mai
Xiaodong
X
Cheng
D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051379:Mice; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000494:pharmacology*
D001381:Azepines; C518299:BIX 01294; D004791:Enzyme Inhibitors; D006657:Histones; D011799:Quinazolines; D056484:Jumonji Domain-Containing Histone Demethylases; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase