An analog of BIX-01294 selectively inhibits a family of histone H3 lysine 9 jumonji demethylases

Anup K. Upadhyay, Dante Rotili, Ji Woong Han, Ruogu Hu, Yanqi Chang, Donatella Labella, Xing Zhang, Young Sup Yoon, Antonello Mai, Xiaodong Cheng

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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.

Original languageEnglish
Pages (from-to)319-327
Number of pages9
JournalJournal of Molecular Biology
Issue number3
Publication statusPublished - 2012 Feb 24


All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

Cite this

Upadhyay, A. K., Rotili, D., Han, J. W., Hu, R., Chang, Y., Labella, D., Zhang, X., Yoon, Y. S., Mai, A., & Cheng, X. (2012). An analog of BIX-01294 selectively inhibits a family of histone H3 lysine 9 jumonji demethylases. Journal of Molecular Biology, 416(3), 319-327.