Targeting DNA-binding drugs to sequence-specific transcription factor.DNA complexes. Differential effects of intercalating and minor groove binding drugs.
Intercalating, minor groove binding, and covalently bonding drugs were evaluated by mobility shift assays for their ability to interfere with transcription factors binding to their respective DNA recognition sequences. The Cys2His2 zinc finger proteins EGR1, WT1, and NIL2A, the basic leucine-zipper protein wbJun/wbFos, and the minor groove binding protein hTBP were chosen as representative transcription factors. Their DNA recognition sites include G/C-rich, mixed, and A/T-rich sequences. The intercalators nogalamycin and hedamycin, and the G/C-specific minor groove binding drug chromomycin A3 were the most potent drugs, preventing transcription factor.DNA complex formation at concentrations less than 1 microM. Similar concentrations of chromomycin A3 disrupted preformed complexes while nogalamycin and hedamycin were 50-fold less potent if proteins were allowed to bind DNA prior to drug treatment. Echinomycin inhibited EGR1.DNA complex formation 50% at 5 microM but had little effect on the formation of NIL2A.DNA complexes. Conversely, doxorubicin was found to inhibit NIL2A complex formation 50% at less than 1 microM, but did not achieve this level of inhibition of EGR1/DNA complex formation even at 50 microM. The A/T-directed minor groove binding drugs, while inhibiting hTBP at submicromolar concentrations, had no effect on either EGR1 or NIL2A.
Welch
J J
JJ
Experimental Therapeutics Department, Roswell Park Cancer Institute, Buffalo, New York 14263.
Rauscher
F J
FJ
Beerman
T A
TA
D000880:Anthraquinones / Q000494:pharmacology; D001483:Base Sequence; D002865:Chromomycins / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004448:Echinomycin / Q000494:pharmacology; D007364:Intercalating Agents / Q000494:pharmacology*; D016350:Leucine Zippers; D008969:Molecular Sequence Data; D009621:Nogalamycin / Q000494:pharmacology; D009838:Oligodeoxyribonucleotides; D014157:Transcription Factors / Q000378:metabolism*; D025721:WT1 Proteins; D016335:Zinc Fingers
D000880:Anthraquinones; D002865:Chromomycins; D004268:DNA-Binding Proteins; D007364:Intercalating Agents; D009838:Oligodeoxyribonucleotides; D014157:Transcription Factors; D025721:WT1 Proteins; C001328:hedamycin; D004448:Echinomycin; D004247:DNA; D009621:Nogalamycin