A Rationally Designed Small Molecule That Inhibits the HIF-1α–ARNT Heterodimer from Binding to DNA in Vivo

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Science's STKE  17 May 2005:
Vol. 2005, Issue 284, pp. pe23
DOI: 10.1126/stke.2842005pe23

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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.

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