Isoform-Selective and Stereoselective Inhibition of Hypoxia Inducible Factor‑2

Hypoxia inducible factor (HIF) transcription
factors reside at
the center of signaling pathways used by mammalian cells to sense
and respond to low oxygen levels. While essential to maintain oxygen
homeostasis, misregulation of HIF protein activity correlates with
tumor development and metastasis. To provide artificial routes to
target misregulated HIF activity, we identified small molecule antagonists
of the HIF-2 transcription factor that bind an internal cavity within
the C-terminal PAS domain of the HIF-2α subunit. Here we describe
a new class of chiral small molecule ligands that provide the highest
affinity binding, the most effective, isoform-selective inhibition
of HIF-2 in cells, and trigger the largest protein conformation changes
reported to date. The current results further illuminate the molecular
mechanism of HIF-2 antagonism and suggest additional routes to develop
higher affinity and potency HIF-2 antagonists.