TY - JOUR
T1 - Isoform-Selective and Stereoselective Inhibition of Hypoxia Inducible Factor-2
AU - Scheuermann, Thomas H.
AU - Stroud, Daniel
AU - Sleet, Christopher E.
AU - Bayeh, Liela
AU - Shokri, Cameron
AU - Wang, Hanzhi
AU - Caldwell, Charles G.
AU - Longgood, Jamie
AU - MacMillan, John B.
AU - Bruick, Richard K.
AU - Gardner, Kevin H.
AU - Tambar, Uttam K.
N1 - Publisher Copyright:
© 2015 American Chemical Society.
PY - 2015/7/30
Y1 - 2015/7/30
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.5b00529
DO - 10.1021/acs.jmedchem.5b00529
M3 - Article
C2 - 26226049
AN - SCOPUS:84939192271
SN - 0022-2623
VL - 58
SP - 5930
EP - 5941
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 15
ER -