Structure-Based Optimization of HIF-2α Agonists That Synergistically Enhance Erythropoietin Production with PHD Inhibitors

Hypoxia-inducible
factor 2α (HIF-2α) is a
crucial transcription
factor regulating various physiological processes, including angiogenesis
and erythropoiesis. The activity of HIF-2α is mainly controlled
through oxygen-dependent protein hydroxylation, mediated by prolyl
hydroxylase domain (PHD) enzymes, leading to subsequent HIF-2α
ubiquitination and degradation. While several small-molecule PHD inhibitors
have already been clinically applied in renal anemia treatment by
indirectly activating the HIF-2α pathway, direct HIF-2α
agonists remain largely unexplored. Here, we developed derivatives
of HIF-2α agonist M1001, identifying SD-10 through
molecular/cellular evaluations. By determining its cocrystal structure
with the heterodimeric HIF-2 protein complex, we precisely characterized
its molecular mechanism of action. Notably, SD-10 exhibited
remarkable synergy with Daprodustat, an approved PHD inhibitor, in
stimulating erythropoietin (EPO) secretion both in cellular models
and animal studies. These findings not only provide insights into
HIF-2α activation mechanism, but also offer a promising lead
compound for developing innovative treatments for renal anemia.