32 Poster Discussion - Discovery and characterization of novel, potent, and selective hypoxiainducible factor (HIF)-2α inhibitors

Abstract

The microenvironment of solid tumors is known to be hypoxic and requires induction of genes associated with metabolism, growth, proliferation, angiogenesis, and erythropoiesis for tumor cells to survive and metastasize. Hypoxia-inducible factors (HIFs) are the master driving force for the cellular response to hypoxia. HIFs are heterodimers composed of an oxygen-sensitive HIF-α subunit (HIF-1α, HIF-2α, and HIF-3α) and a constitutively expressed HIF-1β subunit. Under normoxic conditions, proline residues present in the oxygen-dependent degradation domain of the HIF-α subunits are hydroxylated and subject to recognition and proteasomal degradation via the von Hippel-Lindau (pVHL) E3-ubiquitin ligase complex. When exposed to low oxygen conditions or loss of pVHL function, via mutation or silencing, this process is inhibited, allowing HIF-2α translocation to the nucleus where, in complex with HIF-1β, it promotes transcription of various pro-tumorigenic gene sets. In patients, overexpression of HIF-2α is associated with poor prognosis, and both preclinical and clinical evidence is mounting that suggests inhibiting HIF-2α is an effective strategy to mitigate tumor growth, particularly in clear cell renal cell carcinoma, warranting further development of HIF-2α inhibitors.