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*

*Corresponding author for this work
6 Citations (Scopus)

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 languageEnglish
JournalCancer Letters
Volume530
Pages (from-to)170-180
Number of pages11
ISSN0304-3835
DOIs
Publication statusPublished - 01.04.2022

Research Areas and Centers

  • Research Area: Luebeck Integrated Oncology Network (LION)
  • Centers: University Cancer Center Schleswig-Holstein (UCCSH)

DFG Research Classification Scheme

  • 205-14 Haematology, Oncology

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