ETS transcription factors (TFs) mediate a wide array of cellular functions and are attractive targets for pharmacological control of gene regulation. Members of the ETS-family TFs, such as PU.1 and Ets-1, have winged-helix-turn-helix structures and bind sequence-specifically to 10-bp sites via a recognition helix bound in the major groove of a 5'-GGAA-3' consensus region, with additional contacts with the flanking minor groove. In this work, we have designed a panel of heterocyclic minor groove binders to interfere with ETS TFs binding, and systematically investigated the DNA-TF, DNA-ligand and DNA-TF-ligand interactions. We showed that the DNA binding activities of the TFs are specifically inhibited by the designed ligands bound in the minor groove of adjacent sequences of the consensus site. Moreover, the inhibition properties of the designed ligands are not only generally correlated with their DNA binding affinities but are also strongly dependent on ligand structures and their induced effects on DNA conformation. These results significantly broaden the application of minor groove binders, demonstrate that the reported ligands are powerful inhibitors of ETS TFs that act by targeting the minor groove of flanking sequences, and provide us better understanding for development of effective agents for specific modulation of DNA transcription. (Supported by NIH AI064200 to W.D.W, ACS IRG7700327 to G.M.K.P and NIH AI083803 to J.K.B)

Structure-dependent inhibition of the ETS-family transcription factors by designed minor groove binders

247th National Meeting (2014)

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