Structure-Based Engineering of Irreversible Inhibitors against Histone Lysine Demethylase KDM5A

John R. Horton; Clayton B. Woodcock; Qin Chen; Xu Liu; Xing Zhang; John Shanks; Ganesha Rai; Bryan T. Mott; Daniel J. Jansen; Stephen C. Kales; Mark J. Henderson; Matthew Cyr; Katherine Pohida; Xin Hu; Pranav Shah; Xin Xu; Ajit Jadhav; David J. Maloney; Matthew D. Hall; Anton Simeonov; Haian Fu; Paula M. Vertino; Xiaodong Cheng

doi:10.1021/acs.jmedchem.8b01219

Structure-Based Engineering of Irreversible Inhibitors against Histone Lysine Demethylase KDM5A

John R. Horton, Clayton B. Woodcock, Qin Chen, Xu Liu, Xing Zhang, John Shanks, Ganesha Rai, Bryan T. Mott, Daniel J. Jansen, Stephen C. Kales, Mark J. Henderson, Matthew Cyr, Katherine Pohida, Xin Hu, Pranav Shah, Xin Xu, Ajit Jadhav, David J. Maloney, Matthew D. Hall, Anton SimeonovHaian Fu, Paula M. Vertino, Xiaodong Cheng

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

26 Scopus citations

Abstract

The active sites of hundreds of human α-ketoglutarate (αKG) and Fe(II)-dependent dioxygenases are exceedingly well preserved, which challenges the design of selective inhibitors. We identified a noncatalytic cysteine (Cys481 in KDM5A) near the active sites of KDM5 histone H3 lysine 4 demethylases, which is absent in other histone demethylase families, that could be explored for interaction with the cysteine-reactive electrophile acrylamide. We synthesized analogs of a thienopyridine-based inhibitor chemotype, namely, 2-((3-aminophenyl)(2-(piperidin-1-yl)ethoxy)methyl)thieno[3,2-b]pyridine-7-carboxylic acid (N70) and a derivative containing a (dimethylamino)but-2-enamido)phenyl moiety (N71) designed to form a covalent interaction with Cys481. We characterized the inhibitory and binding activities against KDM5A and determined the cocrystal structures of the catalytic domain of KDM5A in complex with N70 and N71. Whereas the noncovalent inhibitor N70 displayed αKG-competitive inhibition that could be reversed after dialysis, inhibition by N71 was dependent on enzyme concentration and persisted even after dialysis, consistent with covalent modification.

Original language	English (US)
Pages (from-to)	10588-10601
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	61
Issue number	23
DOIs	https://doi.org/10.1021/acs.jmedchem.8b01219
State	Published - Dec 13 2018

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Horton, J. R., Woodcock, C. B., Chen, Q., Liu, X., Zhang, X., Shanks, J., Rai, G., Mott, B. T., Jansen, D. J., Kales, S. C., Henderson, M. J., Cyr, M., Pohida, K., Hu, X., Shah, P., Xu, X., Jadhav, A., Maloney, D. J., Hall, M. D., ... Cheng, X. (2018). Structure-Based Engineering of Irreversible Inhibitors against Histone Lysine Demethylase KDM5A. Journal of Medicinal Chemistry, 61(23), 10588-10601. https://doi.org/10.1021/acs.jmedchem.8b01219

Horton, JR, Woodcock, CB, Chen, Q, Liu, X, Zhang, X, Shanks, J, Rai, G, Mott, BT, Jansen, DJ, Kales, SC, Henderson, MJ, Cyr, M, Pohida, K, Hu, X, Shah, P, Xu, X, Jadhav, A, Maloney, DJ, Hall, MD, Simeonov, A, Fu, H, Vertino, PM & Cheng, X 2018, 'Structure-Based Engineering of Irreversible Inhibitors against Histone Lysine Demethylase KDM5A', Journal of Medicinal Chemistry, vol. 61, no. 23, pp. 10588-10601. https://doi.org/10.1021/acs.jmedchem.8b01219

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title = "Structure-Based Engineering of Irreversible Inhibitors against Histone Lysine Demethylase KDM5A",

abstract = "The active sites of hundreds of human α-ketoglutarate (αKG) and Fe(II)-dependent dioxygenases are exceedingly well preserved, which challenges the design of selective inhibitors. We identified a noncatalytic cysteine (Cys481 in KDM5A) near the active sites of KDM5 histone H3 lysine 4 demethylases, which is absent in other histone demethylase families, that could be explored for interaction with the cysteine-reactive electrophile acrylamide. We synthesized analogs of a thienopyridine-based inhibitor chemotype, namely, 2-((3-aminophenyl)(2-(piperidin-1-yl)ethoxy)methyl)thieno[3,2-b]pyridine-7-carboxylic acid (N70) and a derivative containing a (dimethylamino)but-2-enamido)phenyl moiety (N71) designed to form a covalent interaction with Cys481. We characterized the inhibitory and binding activities against KDM5A and determined the cocrystal structures of the catalytic domain of KDM5A in complex with N70 and N71. Whereas the noncovalent inhibitor N70 displayed αKG-competitive inhibition that could be reversed after dialysis, inhibition by N71 was dependent on enzyme concentration and persisted even after dialysis, consistent with covalent modification.",

author = "Horton, {John R.} and Woodcock, {Clayton B.} and Qin Chen and Xu Liu and Xing Zhang and John Shanks and Ganesha Rai and Mott, {Bryan T.} and Jansen, {Daniel J.} and Kales, {Stephen C.} and Henderson, {Mark J.} and Matthew Cyr and Katherine Pohida and Xin Hu and Pranav Shah and Xin Xu and Ajit Jadhav and Maloney, {David J.} and Hall, {Matthew D.} and Anton Simeonov and Haian Fu and Vertino, {Paula M.} and Xiaodong Cheng",

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doi = "10.1021/acs.jmedchem.8b01219",

language = "English (US)",

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T1 - Structure-Based Engineering of Irreversible Inhibitors against Histone Lysine Demethylase KDM5A

AU - Horton, John R.

AU - Woodcock, Clayton B.

AU - Chen, Qin

AU - Liu, Xu

AU - Zhang, Xing

AU - Shanks, John

AU - Rai, Ganesha

AU - Mott, Bryan T.

AU - Jansen, Daniel J.

AU - Kales, Stephen C.

AU - Henderson, Mark J.

AU - Cyr, Matthew

AU - Pohida, Katherine

AU - Hu, Xin

AU - Shah, Pranav

AU - Xu, Xin

AU - Jadhav, Ajit

AU - Maloney, David J.

AU - Hall, Matthew D.

AU - Simeonov, Anton

AU - Fu, Haian

AU - Vertino, Paula M.

AU - Cheng, Xiaodong

PY - 2018/12/13

Y1 - 2018/12/13

N2 - The active sites of hundreds of human α-ketoglutarate (αKG) and Fe(II)-dependent dioxygenases are exceedingly well preserved, which challenges the design of selective inhibitors. We identified a noncatalytic cysteine (Cys481 in KDM5A) near the active sites of KDM5 histone H3 lysine 4 demethylases, which is absent in other histone demethylase families, that could be explored for interaction with the cysteine-reactive electrophile acrylamide. We synthesized analogs of a thienopyridine-based inhibitor chemotype, namely, 2-((3-aminophenyl)(2-(piperidin-1-yl)ethoxy)methyl)thieno[3,2-b]pyridine-7-carboxylic acid (N70) and a derivative containing a (dimethylamino)but-2-enamido)phenyl moiety (N71) designed to form a covalent interaction with Cys481. We characterized the inhibitory and binding activities against KDM5A and determined the cocrystal structures of the catalytic domain of KDM5A in complex with N70 and N71. Whereas the noncovalent inhibitor N70 displayed αKG-competitive inhibition that could be reversed after dialysis, inhibition by N71 was dependent on enzyme concentration and persisted even after dialysis, consistent with covalent modification.

AB - The active sites of hundreds of human α-ketoglutarate (αKG) and Fe(II)-dependent dioxygenases are exceedingly well preserved, which challenges the design of selective inhibitors. We identified a noncatalytic cysteine (Cys481 in KDM5A) near the active sites of KDM5 histone H3 lysine 4 demethylases, which is absent in other histone demethylase families, that could be explored for interaction with the cysteine-reactive electrophile acrylamide. We synthesized analogs of a thienopyridine-based inhibitor chemotype, namely, 2-((3-aminophenyl)(2-(piperidin-1-yl)ethoxy)methyl)thieno[3,2-b]pyridine-7-carboxylic acid (N70) and a derivative containing a (dimethylamino)but-2-enamido)phenyl moiety (N71) designed to form a covalent interaction with Cys481. We characterized the inhibitory and binding activities against KDM5A and determined the cocrystal structures of the catalytic domain of KDM5A in complex with N70 and N71. Whereas the noncovalent inhibitor N70 displayed αKG-competitive inhibition that could be reversed after dialysis, inhibition by N71 was dependent on enzyme concentration and persisted even after dialysis, consistent with covalent modification.

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 23

ER -

Structure-Based Engineering of Irreversible Inhibitors against Histone Lysine Demethylase KDM5A

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