A small-molecule inhibitor for the potential cancer target HIF-2alpha is reported in a study published this week in Nature Chemical Biology. This compound should enable scientists to determine whether targeting HIF-2alpha is a viable therapeutic strategy in cancer.
HIF-2alpha in combination with its partner ARNT controls gene-expression changes under the low oxygen conditions-called hypoxia-that exist in many cancerous tumors. The genes expressed in response to HIF-2alpha allow cells to adapt to these stressful conditions and may be an important mechanism allowing tumor cells to survive.
Rick Bruick, Kevin Gardner and colleagues report that a small-molecule inhibitor of HIF-2alpha that binds selectively to a cavity inside of this protein, but not to other related proteins such as HIF-1alpha, disrupts the interaction between HIF-2alpha and ARNT. Disruption of this interaction blocks the ability of HIF-2alpha to impact cellular gene expression and also a cell’s response to oxygen stress.