Distamycin A and tallimustine inhibit TBP binding and basal in vitro transcription

The antibiotic distamycin A is a DNA minor groove binding drug (MGB) that recognizes a stretch of a least four ATs. The alkylating benzoyl mustard derivative tallimustine (FCE 24517) has powerfull anti-tumor activity. Using the electrophoretic mobility shift assay (EMSA) we determined that both compounds can prevent binding of TBP and, with 10-fold higher concentration, TBP-TFIIA (DA) and TBP-TRIA-TFIIB (DAB) to a TATA box. Once formed, the DA and DAB complexes are more resistant to MGB challenge. Both drugs can inhibit basal In vitro transcription of a minimal TATA-containlng promoter and similar concentrations are necessary for binding and transcrip-tional inhibition. Tallimustine shows strong selectivity by decreasing only correctly initiated transcripts. Even at high doses (20μM), however, they cannot disturb a competent pre-initiation complex or Pol II progression. This functional in vitro model will provide a way to investigate the activity of sequence-specific DNA binding drugs with potential anti-viral and anti-tumour activity and to develop novel more selective compounds.