title: Structure-dependent inhibition of the ETS-family transcription factor PU.1 by novel heterocyclic diamidines.
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.
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA and Department of Pharmaceutical Sciences, Washington State University, Pullman, WA 99164-6534, USA.
authors.forename: Manoj
authors.initials: M
authors.lastname: Munde
authors.forename: Shuo
authors.initials: S
authors.lastname: Wang
authors.forename: Arvind
authors.initials: A
authors.lastname: Kumar
authors.forename: Chad E
authors.initials: CE
authors.lastname: Stephens
authors.forename: Abdelbasset A
authors.initials: AA
authors.lastname: Farahat
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
authors.forename: W David
authors.initials: WD
authors.lastname: Wilson
authors.forename: Gregory M K
authors.initials: GM
authors.lastname: Poon
mesh_terms: D020856:AT Rich Sequence; D001550:Benzamidines / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D004247:DNA / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D007146:Immunoglobulin lambda-Chains / Q000737:chemistry; D009690:Nucleic Acid Conformation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D001550:Benzamidines; D004247:DNA; D007146:Immunoglobulin lambda-Chains; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1