A rationally designed small molecule that inhibits the HIF-1alpha-ARNT heterodimer from binding to DNA in vivo.
Modern drug development is focused on two steps: the identification of new molecular targets and the development of drugs that affect these targets. A molecular target can be an enzymatic activity or a macromolecular interface that is important in a disease pathway. Current drugs on the market are biased toward targeting cell surface receptors and intracellular enzymatic activities. However, macromolecular interfaces can also serve as potential molecular targets. A recent paper from Kaelin and Dervan's groups examined an underused molecular target-transcription factor DNA binding. To specifically disrupt transcriptional activation, they used a rationally designed small molecule that binds specifically in the minor groove of a DNA sequence that in vivo is bound by a bHLH heterodimer transcription factor.
Vinson
Charles
C
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Vinsonc@mail.nih.gov
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001483:Base Sequence; D015687:Cell Hypoxia; D004247:DNA / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000378:metabolism; D004214:Distamycins / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D005786:Gene Expression Regulation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009429:Netropsin / Q000737:chemistry / Q000494:pharmacology; D009690:Nucleic Acid Conformation / Q000187:drug effects; D009757:Nylons / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D014158:Transcription, Genetic / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
C497396:ARNT protein, human; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004214:Distamycins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009757:Nylons; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D009429:Netropsin; C030000:stallimycin; D004247:DNA