Development of Mithramycin Analogues with Increased Selectivity toward ETS Transcription Factor Expressing Cancers
نویسندگان
چکیده
منابع مشابه
Identification of Mithramycin Analogues with Improved Targeting of the EWS-FLI1 Transcription Factor.
PURPOSE The goal of this study was to identify second-generation mithramycin analogues that better target the EWS-FLI1 transcription factor for Ewing sarcoma. We previously established mithramycin as an EWS-FLI1 inhibitor, but the compound's toxicity prevented its use at effective concentrations in patients. EXPERIMENTAL DESIGN We screened a panel of mithralogs to establish their ability to i...
متن کاملStructures of mithramycin analogues bound to DNA and implications for targeting transcription factor FLI1
Transcription factors have been considered undruggable, but this paradigm has been recently challenged. DNA binding natural product mithramycin (MTM) is a potent antagonist of oncogenic transcription factor EWS-FLI1. Structural details of MTM recognition of DNA, including the FLI1 binding sequence GGA(A/T), are needed to understand how MTM interferes with EWS-FLI1. We report a crystal structure...
متن کاملThe ets-Related Transcription Factor GABP Directs Bidirectional Transcription
Approximately 10% of genes in the human genome are distributed such that their transcription start sites are located less than 1 kb apart on opposite strands. These divergent gene pairs have a single intergenic segment of DNA, which in some cases appears to share regulatory elements, but it is unclear whether these regions represent functional bidirectional promoters or two overlapping promoter...
متن کاملCritical role for the Ets transcription factor ELF-1 in the development of tumor angiogenesis.
The Ets transcription factors regulate a wide variety of biologic processes. Several members have been shown to play a role in regulating angiogenesis and vascular development. For example, the Ets factor ELF-1 is enriched in the developing vasculature of the embryo, where it regulates the expression of the Tie2 gene. We have determined that ELF-1 and Tie2 expression is also enriched in tumor b...
متن کاملIncreased expression of the ETS-related transcription factor FLI-1/ERGB correlates with and can induce the megakaryocytic phenotype.
The human leukemia cell line K562 can be induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) to differentiate along the megakaryocytic pathway, generating morphological changes and increased expression of lineage-specific surface markers. We report that TPA-treated K562 cells also express higher levels of FLI-1/ERGB, a member of the ETS family of transcription factors. Furthermore, introducti...
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ژورنال
عنوان ژورنال: Journal of Medicinal Chemistry
سال: 2018
ISSN: 0022-2623,1520-4804
DOI: 10.1021/acs.jmedchem.8b01107