A synthetic covalent ligand of the C/EBPβ transactivation domain inhibits acute myeloid leukemia cells

Luca Abdel Ghani; Maria V. Yusenko; Daria Frank; Ramkumar Moorthy; John C. Widen; Wolfgang Dörner; Cyrus Khandanpour; Daniel A. Harki; Karl Heinz Klempnauer

doi:10.1016/j.canlet.2022.01.024

A synthetic covalent ligand of the C/EBPβ transactivation domain inhibits acute myeloid leukemia cells

Luca Abdel Ghani, Maria V. Yusenko, Daria Frank, Ramkumar Moorthy, John C. Widen, Wolfgang Dörner, Cyrus Khandanpour, Daniel A. Harki, Karl Heinz Klempnauer

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10 Scopus citations

Abstract

C/EBPβ has recently emerged as a pro-leukemogenic transcription factor that cooperates with oncoprotein MYB to maintain proliferation and differentiation block of AML cells, making C/EBPβ an interesting drug target for AML. Here we have studied the inhibitory potential and biological effects of a synthetic analog of the natural product helenalin, a known inhibitor of C/EBPβ. The synthetic compound inhibits C/EBPβ by covalent binding to cysteine residues in the transactivation domain, thereby causing up-regulation of differentiation-associated genes, cell death and reduced self-renewal potential of AML cells. Suppression of these effects by ectopic expression of C/EBPβ or MYB and gene expression profiling validate C/EBPβ as a relevant target of the helenalin-mimic and highlight its role as a pro-leukemogenic factor. Overall, our work demonstrates that the synthetic helenalin mimic acts as a covalent inhibitor of C/EBPβ and identifies the cysteine residues in the transactivation domain of C/EBPβ as ligandable sites. The helenalin mimic can be considered a potential “lead molecule” but needs further development towards more effective C/EBPβ inhibitors before being used as a therapeutic agent.

Original language	English (US)
Pages (from-to)	170-180
Number of pages	11
Journal	Cancer Letters
Volume	530
DOIs	https://doi.org/10.1016/j.canlet.2022.01.024
State	Published - Apr 1 2022

Bibliographical note

Funding Information:
We thank T.J.Schmidt for providing helenalin acetate, B. Berkenfeld and S. Wulff for expert technical assistance, and H.D.Mootz for support and discussions on mass spectrometry. This work was supported by grants from the Deutsche Krebshilfe and the Deutsche Jose Carreras Leukämie-Stiftung e.V. to K.-H.K., by the Deutsche Forschungsgemeinschaft , the Deutsche Jose Carreras Leukämie-Stiftung e.V. , the Deutsche Krebshilfe , and intramural funding of the University Hospital of Münster to C.K., and by NIH grant R01-GM110129 to D.A.H. We also thank the Core Facility Genomics at the Medical Faculty of the University of Münster for performing next-generation-sequencing and preliminary data analysis.

Publisher Copyright:
© 2022 Elsevier B.V.

Keywords

AML
Apoptosis
C/EBPβ
Covalent inhibitor
Cysteine alkylation
Helenalin mimic
MYB
p300

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.canlet.2022.01.024

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title = "A synthetic covalent ligand of the C/EBPβ transactivation domain inhibits acute myeloid leukemia cells",

abstract = "C/EBPβ has recently emerged as a pro-leukemogenic transcription factor that cooperates with oncoprotein MYB to maintain proliferation and differentiation block of AML cells, making C/EBPβ an interesting drug target for AML. Here we have studied the inhibitory potential and biological effects of a synthetic analog of the natural product helenalin, a known inhibitor of C/EBPβ. The synthetic compound inhibits C/EBPβ by covalent binding to cysteine residues in the transactivation domain, thereby causing up-regulation of differentiation-associated genes, cell death and reduced self-renewal potential of AML cells. Suppression of these effects by ectopic expression of C/EBPβ or MYB and gene expression profiling validate C/EBPβ as a relevant target of the helenalin-mimic and highlight its role as a pro-leukemogenic factor. Overall, our work demonstrates that the synthetic helenalin mimic acts as a covalent inhibitor of C/EBPβ and identifies the cysteine residues in the transactivation domain of C/EBPβ as ligandable sites. The helenalin mimic can be considered a potential “lead molecule” but needs further development towards more effective C/EBPβ inhibitors before being used as a therapeutic agent.",

keywords = "AML, Apoptosis, C/EBPβ, Covalent inhibitor, Cysteine alkylation, Helenalin mimic, MYB, p300",

author = "{Abdel Ghani}, Luca and Yusenko, {Maria V.} and Daria Frank and Ramkumar Moorthy and Widen, {John C.} and Wolfgang D{\"o}rner and Cyrus Khandanpour and Harki, {Daniel A.} and Klempnauer, {Karl Heinz}",

note = "Funding Information: We thank T.J.Schmidt for providing helenalin acetate, B. Berkenfeld and S. Wulff for expert technical assistance, and H.D.Mootz for support and discussions on mass spectrometry. This work was supported by grants from the Deutsche Krebshilfe and the Deutsche Jose Carreras Leuk{\"a}mie-Stiftung e.V. to K.-H.K., by the Deutsche Forschungsgemeinschaft , the Deutsche Jose Carreras Leuk{\"a}mie-Stiftung e.V. , the Deutsche Krebshilfe , and intramural funding of the University Hospital of M{\"u}nster to C.K., and by NIH grant R01-GM110129 to D.A.H. We also thank the Core Facility Genomics at the Medical Faculty of the University of M{\"u}nster for performing next-generation-sequencing and preliminary data analysis. Publisher Copyright: {\textcopyright} 2022 Elsevier B.V.",

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doi = "10.1016/j.canlet.2022.01.024",

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T1 - A synthetic covalent ligand of the C/EBPβ transactivation domain inhibits acute myeloid leukemia cells

AU - Abdel Ghani, Luca

AU - Yusenko, Maria V.

AU - Frank, Daria

AU - Moorthy, Ramkumar

AU - Widen, John C.

AU - Dörner, Wolfgang

AU - Khandanpour, Cyrus

AU - Harki, Daniel A.

AU - Klempnauer, Karl Heinz

N1 - Funding Information: We thank T.J.Schmidt for providing helenalin acetate, B. Berkenfeld and S. Wulff for expert technical assistance, and H.D.Mootz for support and discussions on mass spectrometry. This work was supported by grants from the Deutsche Krebshilfe and the Deutsche Jose Carreras Leukämie-Stiftung e.V. to K.-H.K., by the Deutsche Forschungsgemeinschaft , the Deutsche Jose Carreras Leukämie-Stiftung e.V. , the Deutsche Krebshilfe , and intramural funding of the University Hospital of Münster to C.K., and by NIH grant R01-GM110129 to D.A.H. We also thank the Core Facility Genomics at the Medical Faculty of the University of Münster for performing next-generation-sequencing and preliminary data analysis. Publisher Copyright: © 2022 Elsevier B.V.

PY - 2022/4/1

Y1 - 2022/4/1

N2 - C/EBPβ has recently emerged as a pro-leukemogenic transcription factor that cooperates with oncoprotein MYB to maintain proliferation and differentiation block of AML cells, making C/EBPβ an interesting drug target for AML. Here we have studied the inhibitory potential and biological effects of a synthetic analog of the natural product helenalin, a known inhibitor of C/EBPβ. The synthetic compound inhibits C/EBPβ by covalent binding to cysteine residues in the transactivation domain, thereby causing up-regulation of differentiation-associated genes, cell death and reduced self-renewal potential of AML cells. Suppression of these effects by ectopic expression of C/EBPβ or MYB and gene expression profiling validate C/EBPβ as a relevant target of the helenalin-mimic and highlight its role as a pro-leukemogenic factor. Overall, our work demonstrates that the synthetic helenalin mimic acts as a covalent inhibitor of C/EBPβ and identifies the cysteine residues in the transactivation domain of C/EBPβ as ligandable sites. The helenalin mimic can be considered a potential “lead molecule” but needs further development towards more effective C/EBPβ inhibitors before being used as a therapeutic agent.

AB - C/EBPβ has recently emerged as a pro-leukemogenic transcription factor that cooperates with oncoprotein MYB to maintain proliferation and differentiation block of AML cells, making C/EBPβ an interesting drug target for AML. Here we have studied the inhibitory potential and biological effects of a synthetic analog of the natural product helenalin, a known inhibitor of C/EBPβ. The synthetic compound inhibits C/EBPβ by covalent binding to cysteine residues in the transactivation domain, thereby causing up-regulation of differentiation-associated genes, cell death and reduced self-renewal potential of AML cells. Suppression of these effects by ectopic expression of C/EBPβ or MYB and gene expression profiling validate C/EBPβ as a relevant target of the helenalin-mimic and highlight its role as a pro-leukemogenic factor. Overall, our work demonstrates that the synthetic helenalin mimic acts as a covalent inhibitor of C/EBPβ and identifies the cysteine residues in the transactivation domain of C/EBPβ as ligandable sites. The helenalin mimic can be considered a potential “lead molecule” but needs further development towards more effective C/EBPβ inhibitors before being used as a therapeutic agent.

KW - AML

KW - Apoptosis

KW - C/EBPβ

KW - Covalent inhibitor

KW - Cysteine alkylation

KW - Helenalin mimic

KW - MYB

KW - p300

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M3 - Article

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SN - 0304-3835

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JO - Cancer Letters

JF - Cancer Letters

ER -

A synthetic covalent ligand of the C/EBPβ transactivation domain inhibits acute myeloid leukemia cells

Abstract

Bibliographical note

Keywords

UN SDGs

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