Inhibition of histone lysine methyltransferases G9a and GLP by ejection of structural Zn(II)

Danny C. Lenstra, Abbas H.K. Al Temimi, Jasmin Mecinović*

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Resumé

Histone lysine methyltransferases G9a and GLP are validated targets for the development of new epigenetic drugs. Most, if not all, inhibitors of G9a and GLP target the histone substrate binding site or/and the S-adenosylmethionine cosubstrate binding site. Here, we report an alternative approach for inhibiting the methyltransferase activity of G9a and GLP. For proper folding and enzymatic activity, G9a and GLP contain structural zinc fingers, one of them being adjacent to the S-adenosylmethionine binding site. Our work demonstrates that targeting these labile zinc fingers with electrophilic small molecules results in ejection of structural zinc ions, and consequently inhibition of the methyltransferase activity. Very effective Zn(II) ejection and inhibition of G9a and GLP was observed with clinically used ebselen, disulfiram and cisplatin.

OriginalsprogEngelsk
TidsskriftBioorganic and Medicinal Chemistry Letters
Vol/bind28
Udgave nummer7
Sider (fra-til)1234-1238
ISSN0960-894X
DOI
StatusUdgivet - 15. apr. 2018
Udgivet eksterntJa

Fingeraftryk

Histone-Lysine N-Methyltransferase
Zinc
S-Adenosylmethionine
Binding Sites
Methyltransferases
Disulfiram
Epigenomics
Histones
Cisplatin
Ions
Molecules
Substrates
Pharmaceutical Preparations

Citer dette

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title = "Inhibition of histone lysine methyltransferases G9a and GLP by ejection of structural Zn(II)",
abstract = "Histone lysine methyltransferases G9a and GLP are validated targets for the development of new epigenetic drugs. Most, if not all, inhibitors of G9a and GLP target the histone substrate binding site or/and the S-adenosylmethionine cosubstrate binding site. Here, we report an alternative approach for inhibiting the methyltransferase activity of G9a and GLP. For proper folding and enzymatic activity, G9a and GLP contain structural zinc fingers, one of them being adjacent to the S-adenosylmethionine binding site. Our work demonstrates that targeting these labile zinc fingers with electrophilic small molecules results in ejection of structural zinc ions, and consequently inhibition of the methyltransferase activity. Very effective Zn(II) ejection and inhibition of G9a and GLP was observed with clinically used ebselen, disulfiram and cisplatin.",
keywords = "Cisplatin, Disulfiram, Ebselen, Lysine methyltransferase, Zinc ejection",
author = "Lenstra, {Danny C.} and {Al Temimi}, {Abbas H.K.} and Jasmin Mecinović",
year = "2018",
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Inhibition of histone lysine methyltransferases G9a and GLP by ejection of structural Zn(II). / Lenstra, Danny C.; Al Temimi, Abbas H.K.; Mecinović, Jasmin.

I: Bioorganic and Medicinal Chemistry Letters, Bind 28, Nr. 7, 15.04.2018, s. 1234-1238.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Inhibition of histone lysine methyltransferases G9a and GLP by ejection of structural Zn(II)

AU - Lenstra, Danny C.

AU - Al Temimi, Abbas H.K.

AU - Mecinović, Jasmin

PY - 2018/4/15

Y1 - 2018/4/15

N2 - Histone lysine methyltransferases G9a and GLP are validated targets for the development of new epigenetic drugs. Most, if not all, inhibitors of G9a and GLP target the histone substrate binding site or/and the S-adenosylmethionine cosubstrate binding site. Here, we report an alternative approach for inhibiting the methyltransferase activity of G9a and GLP. For proper folding and enzymatic activity, G9a and GLP contain structural zinc fingers, one of them being adjacent to the S-adenosylmethionine binding site. Our work demonstrates that targeting these labile zinc fingers with electrophilic small molecules results in ejection of structural zinc ions, and consequently inhibition of the methyltransferase activity. Very effective Zn(II) ejection and inhibition of G9a and GLP was observed with clinically used ebselen, disulfiram and cisplatin.

AB - Histone lysine methyltransferases G9a and GLP are validated targets for the development of new epigenetic drugs. Most, if not all, inhibitors of G9a and GLP target the histone substrate binding site or/and the S-adenosylmethionine cosubstrate binding site. Here, we report an alternative approach for inhibiting the methyltransferase activity of G9a and GLP. For proper folding and enzymatic activity, G9a and GLP contain structural zinc fingers, one of them being adjacent to the S-adenosylmethionine binding site. Our work demonstrates that targeting these labile zinc fingers with electrophilic small molecules results in ejection of structural zinc ions, and consequently inhibition of the methyltransferase activity. Very effective Zn(II) ejection and inhibition of G9a and GLP was observed with clinically used ebselen, disulfiram and cisplatin.

KW - Cisplatin

KW - Disulfiram

KW - Ebselen

KW - Lysine methyltransferase

KW - Zinc ejection

U2 - 10.1016/j.bmcl.2018.02.043

DO - 10.1016/j.bmcl.2018.02.043

M3 - Journal article

VL - 28

SP - 1234

EP - 1238

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

SN - 0960-894X

IS - 7

ER -