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

doi:10.1016/j.jmb.2011.12.036

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

BioMedical Science Institute

Research output: Contribution to journal › Article › peer-review

45 Citations (Scopus)

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.

Original language	English
Pages (from-to)	319-327
Number of pages	9
Journal	Journal of Molecular Biology
Volume	416
Issue number	3
DOIs	https://doi.org/10.1016/j.jmb.2011.12.036
Publication status	Published - 2012 Feb 24

Bibliographical note

Funding Information:
We thank Dr. John R. Horton for maintaining local X-ray facility and help with X-ray data collection in synchrotron, Dr. Justin E. Jones for comments and Dr. Robert A. Copeland for suggestion of calculating K i app values. The Department of Biochemistry at the Emory University School of Medicine supported the use of the Southeast Regional Collaborative Access Team synchrotron beamline at the Advanced Photon Source of Argonne National Laboratory, local X-ray facility and matrix-assisted laser desorption/ionization–time of flight mass spectrometry. This work was supported by National Institutes of Health grants ( GM068680-07 to X.C. and GM092035-01 to X.C. and Y.Y.), by PRIN 2009PX2T2E and by the FP7 Project BLUEPRINT/282510 to A.M. X.C. is a Georgia Research Alliance Eminent Scholar.

All Science Journal Classification (ASJC) codes

Structural Biology
Molecular Biology

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10.1016/j.jmb.2011.12.036

Cite this

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

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.",

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

note = "Funding Information: We thank Dr. John R. Horton for maintaining local X-ray facility and help with X-ray data collection in synchrotron, Dr. Justin E. Jones for comments and Dr. Robert A. Copeland for suggestion of calculating K i app values. The Department of Biochemistry at the Emory University School of Medicine supported the use of the Southeast Regional Collaborative Access Team synchrotron beamline at the Advanced Photon Source of Argonne National Laboratory, local X-ray facility and matrix-assisted laser desorption/ionization–time of flight mass spectrometry. This work was supported by National Institutes of Health grants ( GM068680-07 to X.C. and GM092035-01 to X.C. and Y.Y.), by PRIN 2009PX2T2E and by the FP7 Project BLUEPRINT/282510 to A.M. X.C. is a Georgia Research Alliance Eminent Scholar. ",

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AU - Upadhyay, Anup K.

AU - Rotili, Dante

AU - Han, Ji Woong

AU - Hu, Ruogu

AU - Chang, Yanqi

AU - Labella, Donatella

AU - Zhang, Xing

AU - Yoon, Young Sup

AU - Mai, Antonello

AU - Cheng, Xiaodong

N1 - Funding Information: We thank Dr. John R. Horton for maintaining local X-ray facility and help with X-ray data collection in synchrotron, Dr. Justin E. Jones for comments and Dr. Robert A. Copeland for suggestion of calculating K i app values. The Department of Biochemistry at the Emory University School of Medicine supported the use of the Southeast Regional Collaborative Access Team synchrotron beamline at the Advanced Photon Source of Argonne National Laboratory, local X-ray facility and matrix-assisted laser desorption/ionization–time of flight mass spectrometry. This work was supported by National Institutes of Health grants ( GM068680-07 to X.C. and GM092035-01 to X.C. and Y.Y.), by PRIN 2009PX2T2E and by the FP7 Project BLUEPRINT/282510 to A.M. X.C. is a Georgia Research Alliance Eminent Scholar.

PY - 2012/2/24

Y1 - 2012/2/24

N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

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