Anemia is a common and significant complication of chronic kidney disease (CKD), leading to multiple adverse
consequences including, increased hospitalizations and mortality, cardiovascular disease, cognitive
impairment, and diminished quality of life.
Nearly half of all patients with stage 3-5 CKD experience anemia. In
these patients, the underlying cause is from the diminished kidney production of erythropoietin (EPO). EPO is
a glycoprotein cytokine secreted by the kidney in response to low oxygen stress to stimulate red blood cell
production in the bone marrow. The hypoxia-inducible factor-2 alpha (HIF-2¿) forms heterodimer with aryl
hydrocarbon receptor nuclear translocator (ARNT) to form a productive transcription factor that drives
physiological EPO expression by binding to the hypoxia response element (HRE) upstream of the EPO gene.
detailed structural elucidation of the multi-domain heterodimeric complex of HIF-2¿/ARNT has allowed
Certain small-molecules such as PT2385 and OX3 can act as
inhibitors of HIF-2¿ by disrupting the HIF-2¿/ARNT heterodimer. We hypothesize that other small-molecules
can be identified to stabilize the HIF-2¿/ARNT heterodimer and act as activators. However, no attempts have
yet been undertaken to identify HIF-2¿ activators. Driven by our recent crystallographic discovery of multiple
ligand-binding cavities within this heterodimer, we designed and conducted small pilot screens based on a
sensitive biochemical protein-protein interaction assay. These efforts allowed the identification of small-
molecules that biochemically stabilize the HIF-2¿/ARNT heterodimer and led to enhanced EPO expression
within cells. In response to
new appreciation for its drug-binding potentials.
NIDDK PA-16-374, we now propose to conduct a comprehensive high-throughput
screen using a 350,000-compound library, together with the suite of secondary and tertiary confirmatory
assays to identify HIF-2¿/-ARNT selective activators for preclinical development. These activators will have
substantial advantages over the current treatments involving recombinant EPO injections, and should be
significantly safer and more effective than the prolyl-hydroxylase inhibitors undergoing development.