Development of Mithramycin Analogues with Increased Selectivity toward ETS Transcription Factor Expressing Cancers

Prithiba Mitra, Joseph M. Eckenrode, Abhisek Mandal, Amit K. Jha, Shaimaa M. Salem, Markos Leggas, Jürgen Rohr

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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.

Original languageEnglish
Pages (from-to)8001-8016
Number of pages16
JournalJournal of Medicinal Chemistry
Volume61
Issue number17
DOIs
StatePublished - Sep 13 2018

Bibliographical note

Publisher Copyright:
© 2018 American Chemical Society.

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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