Journal
MOLECULES
Volume 27, Issue 7, Pages -Publisher
MDPI
DOI: 10.3390/molecules27072077
Keywords
transcription factor; MYB; C/EBP beta; p300; cancer; leukemia; natural product; sesquiterpene lactone; withanolide; withaferin A; celastrol; naphthoquinone; plumbagin
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The transcription factor MYB plays an important role in hematopoietic progenitor cells. It cooperates with CCAAT box/enhancer binding protein (C/EBP) to form a transcriptional module, and is involved in the development of human leukemia, specifically T-ALL and AML. Inhibitors that target the MYB-C/EBP beta-p300 transcriptional module may have potential as anti-tumor drugs. Natural products belonging to different structural classes have been identified as inhibitors, and this review provides an overview of these inhibitors and their mechanisms of action, as well as their potential for further development.
The transcription factor MYB is expressed predominantly in hematopoietic progenitor cells, where it plays an essential role in the development of most lineages of the hematopoietic system. In the myeloid lineage, MYB is known to cooperate with members of the CCAAT box/enhancer binding protein (C/EBP) family of transcription factors. MYB and C/EBPs interact with the co-activator p300 or its paralog CREB-binding protein (CBP), to form a transcriptional module involved in myeloid-specific gene expression. Recent work has demonstrated that MYB is involved in the development of human leukemia, especially in acute T-cell leukemia (T-ALL) and acute myeloid leukemia (AML). Chemical entities that inhibit the transcriptional activity of the MYB-C/EBP beta-p300 transcription module may therefore be of use as potential anti-tumour drugs. In searching for small molecule inhibitors, studies from our group over the last 10 years have identified natural products belonging to different structural classes, including various sesquiterpene lactones, a steroid lactone, quinone methide triterpenes and naphthoquinones that interfere with the activity of this transcriptional module in different ways. This review gives a comprehensive overview on the various classes of inhibitors and the inhibitory mechanisms by which they affect the MYB-C/EBP beta-p300 transcriptional module as a potential anti-tumor target. We also focus on the current knowledge on structure-activity relationships underlying these biological effects and on the potential of these compounds for further development.
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