| Literature DB >> 22227394 |
Anup K Upadhyay1, Dante Rotili, Ji Woong Han, Ruogu Hu, Yanqi Chang, Donatella Labella, Xing Zhang, Young-Sup Yoon, Antonello Mai, Xiaodong Cheng.
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.Entities:
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Year: 2011 PMID： 22227394 PMCID： PMC3280428 DOI： 10.1016/j.jmb.2011.12.036
Source DB: PubMed Journal: J Mol Biol ISSN： 0022-2836 Impact factor: 5.469