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

JOURNAL OF MOLECULAR BIOLOGY

卷:416

Article

Upadhyay, Anup K.¹  Rotili, Dante⁴  Han, Ji Woong²  Hu, Ruogu^1,3  Chang, Yanqi¹  Labella, Donatella⁴  Zhang, Xing¹  Yoon, Young-sup²  Mai, Antonello⁴  Cheng, Xiaodong¹ 

[1] Emory Univ, Sch Med, Dept Biochem, Atlanta, GA 30322 USA

[2] Emory Univ, Sch Med, Dept Med, Div Cardiol, Atlanta, GA 30322 USA

[3] Emory Univ, Sch Med, Biochem Cell & Dev Biol Grad Program, Atlanta, GA 30322 USA

[4] Univ Roma La Sapienza, Ist Pasteur Fdn Cenci Bolognetti, Dipartimento Chim & Tecnol Farmaco, I-00185 Rome, Italy

关键词: epigenetics;    histone lysine demethylation;    enzymatic inhibition;    BIX analogs;   

DOI  :  10.1016/j.jmb.2011.12.036

来源: Elsevier

【 摘 要 】

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. (C) 2011 Elsevier Ltd. All rights reserved.

【 授权许可】

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