Abstract
Mithramycin A (1) was identified as the top potential inhibitor of the aberrant ETS transcription factor EWS-FLI1, which causes Ewing sarcoma. Unfortunately, 1 has a narrow therapeutic window, compelling us to seek less toxic and more selective analogues. Here, we used MTMSA (2) to generate analogues via peptide coupling and fragment-based drug development strategies. Cytotoxicity assays in ETS and non-ETS dependent cell lines identified two dipeptide analogues, 60 and 61, with 19.1- and 15.6-fold selectivity, respectively, compared to 1.5-fold for 1. Importantly, the cytotoxicity of 60 and 61 is <100 nM in ETS cells. Molecular assays demonstrated the inhibitory capacity of these analogues against EWS-FLI1 mediated transcription in Ewing sarcoma. Structural analysis shows that positioning the tryptophan residue in a distal position improves selectivity, presumably via interaction with the ETS transcription factor. Thus, these analogues may present new ways to target transcription factors for clinical use.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Antibiotics, Antineoplastic / chemistry
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacology*
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Bone Neoplasms / drug therapy
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Bone Neoplasms / metabolism
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Bone Neoplasms / pathology
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Cell Proliferation / drug effects*
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Drug Development*
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Gene Expression Regulation, Neoplastic
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Humans
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Male
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Molecular Structure
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Oncogene Proteins, Fusion / antagonists & inhibitors*
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism
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Plicamycin / analogs & derivatives*
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Prostatic Neoplasms / drug therapy
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Proto-Oncogene Protein c-fli-1 / antagonists & inhibitors*
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Proto-Oncogene Protein c-fli-1 / genetics
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Proto-Oncogene Protein c-fli-1 / metabolism
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Proto-Oncogene Proteins c-ets / antagonists & inhibitors*
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Proto-Oncogene Proteins c-ets / genetics
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Proto-Oncogene Proteins c-ets / metabolism
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RNA-Binding Protein EWS / antagonists & inhibitors*
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RNA-Binding Protein EWS / genetics
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RNA-Binding Protein EWS / metabolism
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Sarcoma, Ewing / drug therapy*
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Sarcoma, Ewing / metabolism
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Sarcoma, Ewing / pathology
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Tumor Cells, Cultured
Substances
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Antibiotics, Antineoplastic
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Antineoplastic Agents
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EWS-FLI fusion protein
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Oncogene Proteins, Fusion
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Proto-Oncogene Protein c-fli-1
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Proto-Oncogene Proteins c-ets
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RNA-Binding Protein EWS
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Plicamycin