Transcription factors as targets for DNA-interacting drugs.
Gene expression, both tissue specific or inducible, is controlled at the level of transcription by various transcription factors interacting with specific sequences of DNA. Anticancer drugs and other potential therapeutic agents alter interactions of regulatory proteins with DNA by a variety of different mechanisms. The main ones, considered in the review, are: i) competition for the transcription factor DNA binding sequences by drugs that interact non-covalently with DNA (e.g. anthracyclines, acridines, actinomycin D, pyrrole antibiotics and their polyamide derivatives); ii) covalent modifications of DNA by alkylating agents (e.g. nitrogen mustards, cisplatin) that prevent transcription factors from recognizing their specific sequences, or that result in multiple "unnatural" binding sites in DNA which hijack the transcription factors, thus decreasing their availability in the nucleus; iii) competition with binding sites on the transcription factors by synthetic oligonucleotides or peptide nucleic acids in an antigene strategy. The latter compounds may also compete for binding sites on regulatory proteins, acting as decoys to lower their active concentration in the cell. In this review, we have summarized recent advances which have been made towards understanding the above mechanisms by which small molecules interfere with the function of transcription factors.
Gniazdowski
Marek
M
Department of Medicinal Chemistry, Institute of Physiology and Biochemistry, Medical University of Lódz, Poland. magn@csk.am.lodz.pl
Denny
William A
WA
Nelson
Stephanie M
SM
Czyz
Malgorzata
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000378:metabolism*
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D007364:Intercalating Agents; D016376:Oligonucleotides, Antisense; D014157:Transcription Factors; D004247:DNA