Structure-dependent inhibition of the ETS-family transcription factor PU.1 by novel heterocyclic diamidines

Manoj Munde, Shuo Wang, Arvind Kumar, Chad E. Stephens, Abdelbasset A. Farahat, David W. Boykin, W. David Wilson, Gregory M.K. Poon

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

ETS transcription factors mediate a wide array of cellular functions and are attractive targets for pharmacological control of gene regulation. We report the inhibition of the ETS-family member PU.1 with a panel of novel heterocyclic diamidines. These diamidines are derivatives of furamidine (DB75) in which the central furan has been replaced with selenophene and/or one or both of the bridging phenyl has been replaced with benzimidazole. Like all ETS proteins, PU.1 binds sequence specifically to 10-bp sites by inserting a recognition helix into the major groove of a 5′-GGAA-3′ consensus, accompanied by contacts with the flanking minor groove. We showed that diamidines target the minor groove of AT-rich sequences on one or both sides of the consensus and disrupt PU.1 binding. Although all of the diamidines bind to one or both of the expected sequences within the binding site, considerable heterogeneity exists in terms of stoichiometry, site-site interactions and induced DNA conformation. We also showed that these compounds accumulate in live cell nuclei and inhibit PU.1-dependent gene transactivation. This study demonstrates that heterocyclic diamidines are capable of inhibiting PU.1 by targeting the flanking sequences and supports future efforts to develop agents for inhibiting specific members of the ETS family.

Original languageEnglish (US)
Pages (from-to)1379-1390
Number of pages12
JournalNucleic Acids Research
Volume42
Issue number2
DOIs
StatePublished - Feb 10 2014

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Pentamidine
Consensus
AT Rich Sequence
Nucleic Acid Conformation
Cell Nucleus
Transcriptional Activation
Genes
Transcription Factors
Binding Sites
Inhibition (Psychology)
proto-oncogene protein Spi-1
Pharmacology

ASJC Scopus subject areas

  • Genetics

Cite this

Structure-dependent inhibition of the ETS-family transcription factor PU.1 by novel heterocyclic diamidines. / Munde, Manoj; Wang, Shuo; Kumar, Arvind; Stephens, Chad E.; Farahat, Abdelbasset A.; Boykin, David W.; Wilson, W. David; Poon, Gregory M.K.

In: Nucleic Acids Research, Vol. 42, No. 2, 10.02.2014, p. 1379-1390.

Research output: Contribution to journalArticle

Munde, M, Wang, S, Kumar, A, Stephens, CE, Farahat, AA, Boykin, DW, Wilson, WD & Poon, GMK 2014, 'Structure-dependent inhibition of the ETS-family transcription factor PU.1 by novel heterocyclic diamidines', Nucleic Acids Research, vol. 42, no. 2, pp. 1379-1390. https://doi.org/10.1093/nar/gkt955
Munde, Manoj ; Wang, Shuo ; Kumar, Arvind ; Stephens, Chad E. ; Farahat, Abdelbasset A. ; Boykin, David W. ; Wilson, W. David ; Poon, Gregory M.K. / Structure-dependent inhibition of the ETS-family transcription factor PU.1 by novel heterocyclic diamidines. In: Nucleic Acids Research. 2014 ; Vol. 42, No. 2. pp. 1379-1390.
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