Allosteric inhibition of hypoxia inducible factor-2 with small molecules

Abstract

Hypoxia Inducible Factors (HIFs) are heterodimeric transcription factors induced in many cancers where they frequently promote the expression of many protumorigenic pathways. Though transcription factors are typically considered "undruggable", the PAS-B domain of the HIF-2α subunit contains a large cavity within its hydrophobic core that offers a unique foothold for smallmolecule regulation. Here we identify artificial ligands that bind within this pocket and characterize the resulting structural and functional changes caused by binding. Notably, these ligands antagonize HIF-2 heterodimerization and DNA-binding activity in vitro and in cultured cells, reducing HIF-2 target gene expression. Despite the high identity between HIF-2α and HIF-1α, these ligands are highly selective and do not affect HIF-1 function. These chemical tools establish the molecular basis for selective regulation of HIF-2, providing potential therapeutic opportunities to intervene in HIF-2-driven tumors such as renal cell carcinomas.

Pharmacological HIF2α inhibition improves VHL disease–associated phenotypes in zebrafish model

“…The HIF2α inhibitors that we discovered function by specifically repressing the translation of this transcription factor. To the best of our knowledge, the only other available small molecule with specific HIF2α inhibitor activity uses a different mode of action; it disrupts HIF2α-ARNT heterodimerization (43). No data on the efficacy of this compound in vivo have been published.…”

Intestine-specific Disruption of Hypoxia-inducible Factor (HIF)-2α Improves Anemia in Sickle Cell Disease

“…Targeting intestinal HIF-2␣ may reduce the need of repeated blood transfusions or pharmacologic iron chelation. With a recent discovery of orally bioavailable HIF-2␣-specific inhibitors (24), the present data suggest that use of these inhibitors could be a novel and effective treatment strategy for SCD. …”

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

“…This makes it possible to design specific inhibitors simply through protein sequence analysis because the small-molecule binding sites have certain peptide sequence criteria. Also, HIF dimer inhibitors as well as HIF DNA-binding inhibitors have been reported (168,169). In addition, dominant negative peptides mimicking the HLH domain show a significant impact on E2A dimerization (170).…”