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.
Bibliographical noteFunding 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.
© 2022 Elsevier B.V.
- Covalent inhibitor
- Cysteine alkylation
- Helenalin mimic
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't