دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: A synthetic covalent ligand of the C/EBPβ transactivation domain inhibits acute myeloid leukemia cells.
المؤلفون: Abdel Ghani L; Institute for Biochemistry, Westfälische-Wilhelms-Universität, Münster, Germany., Yusenko MV; Institute for Biochemistry, Westfälische-Wilhelms-Universität, Münster, Germany., Frank D; Department of Medicine A, Hematology and Oncology, University Hospital, Westfälische-Wilhelms-Universität, Münster, Germany., Moorthy R; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, USA., Widen JC; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, USA., Dörner W; Institute for Biochemistry, Westfälische-Wilhelms-Universität, Münster, Germany., Khandanpour C; Department of Medicine A, Hematology and Oncology, University Hospital, Westfälische-Wilhelms-Universität, Münster, Germany., Harki DA; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, USA., Klempnauer KH; Institute for Biochemistry, Westfälische-Wilhelms-Universität, Münster, Germany. Electronic address: klempna@uni-muenster.de.
المصدر: Cancer letters [Cancer Lett] 2022 Apr 01; Vol. 530, pp. 170-180. Date of Electronic Publication: 2022 Jan 22.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Elsevier Science Ireland Country of Publication: Ireland NLM ID: 7600053 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-7980 (Electronic) Linking ISSN: 03043835 NLM ISO Abbreviation: Cancer Lett Subsets: MEDLINE
أسماء مطبوعة: Publication: Limerick : Elsevier Science Ireland
Original Publication: Amsterdam, Elsevier/North-Holland.
مواضيع طبية MeSH: CCAAT-Enhancer-Binding Protein-beta/*genetics , Leukemia, Myeloid, Acute/*drug therapy , Sesquiterpenes, Guaiane/*pharmacology , Transcriptional Activation/*drug effects, 3T3 Cells ; Animals ; Cell Differentiation/drug effects ; Cell Differentiation/genetics ; Cell Line ; Cell Line, Tumor ; Gene Expression Regulation/drug effects ; Gene Expression Regulation/genetics ; HEK293 Cells ; HL-60 Cells ; Humans ; Leukemia, Myeloid, Acute/genetics ; Ligands ; Mice ; Mice, Inbred C57BL ; Promoter Regions, Genetic/drug effects ; Promoter Regions, Genetic/genetics ; THP-1 Cells
مستخلص: 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.
(Copyright © 2022 Elsevier B.V. All rights reserved.)
معلومات مُعتمدة: R01 GM110129 United States GM NIGMS NIH HHS
فهرسة مساهمة: Keywords: AML; Apoptosis; C/EBPβ; Covalent inhibitor; Cysteine alkylation; Helenalin mimic; MYB; p300
المشرفين على المادة: 0 (CCAAT-Enhancer-Binding Protein-beta)
0 (CEBPB protein, human)
0 (Ligands)
0 (Sesquiterpenes, Guaiane)
4GUY9L896T (helenalin)
تواريخ الأحداث: Date Created: 20220125 Date Completed: 20220308 Latest Revision: 20220308
رمز التحديث: 20240628
DOI: 10.1016/j.canlet.2022.01.024
PMID: 35077804
قاعدة البيانات: MEDLINE
الوصف
تدمد:1872-7980
DOI:10.1016/j.canlet.2022.01.024