Targeting the DNA-binding activity of the human ERG transcription factor using new heterocyclic dithiophene diamidines

Raja Nhili, Paul Peixoto, Sabine Depauw, Sébastien Flajollet, Xavier Dezitter, Manoj M. Munde, Mohamed A. Ismail, Arvind Kumar, Abdelbasset A. Farahat, Chad E. Stephens, Martine Duterque-Coquillaud, W. David Wilson, David W. Boykin, Marie Hélène David-Cordonnier

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


Direct modulation of gene expression by targeting oncogenic transcription factors is a new area of research for cancer treatment. ERG, an ETS-family transcription factor, is commonly over-expressed or translocated in leukaemia and prostate carcinoma. In this work, we selected the di-(thiophene-phenyl- amidine) compound DB1255 as an ERG/DNA binding inhibitor using a screening test of synthetic inhibitors of the ERG/DNA interaction followed by electrophoretic mobility shift assays (EMSA) validation. Spectrometry, footprint and biosensor-surface plasmon resonance analyses of the DB1255/DNA interaction evidenced sequence selectivity and groove binding as dimer. Additional EMSA evidenced the precise DNA-binding sequence required for optimal DB1255/DNA binding and thus for an efficient ERG/DNA complex inhibition. We further highlighted the structure activity relationships from comparison with derivatives. In cellulo luciferase assay confirmed this modulation both with the constructed optimal sequences and the Osteopontin promoter known to be regulated by ERG and which ERG-binding site was protected from DNaseI digestion on binding of DB1255. These data showed for the first time the ERG/DNA complex modulation, both in vitro and in cells, by a heterocyclic diamidine that specifically targets a portion of the ERG DNA recognition site.

Original languageEnglish (US)
Pages (from-to)125-138
Number of pages14
JournalNucleic Acids Research
Issue number1
StatePublished - Jan 2013
Externally publishedYes

ASJC Scopus subject areas

  • Genetics


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