Pharmacological exploitation of the HIF signalling pathway
Genetic mutations that operate from birth may invoke developmental influences that contribute to a protective phenotype. Nonetheless the enrichment of genes for EPAS1 and EGLN1 in adapted highlanders has given added weight to evaluating HIF signalling as a target for pulmonary hypertension. Bigham and Lee (Bigham & Lee, 2014) discuss the possible combinations of loss-of-function and gain-of-function EPAS1 and EGLN1 alleles to explain Tibetan adaptation and suggest it may be necessary to target both HIF2α and PHD2 to reproduce the Tibetan phenotype (Figure 1). To date, most progress has been made with exploring inhibition of HIF2α as a drug target for pulmonary hypertension.
As a transcription factor that activates gene expression through protein-protein interactions, HIF2α was generally regarded as intractable for small molecule inhibition. But biophysical studies have revealed that the inner core of the PAS-B domain of HIF2α possesses a hydrophobic cavity that can bind small molecules that allosterically disrupt its dimerization to ARNT and thereby block transcriptional activity (Scheuermann, Tomchick, Machius, Guo, Bruick & Gardner, 2009). A cellular screening approach for HIF2α inhibitors has identified Compound 76 (C76) as a useful tool compound (Zimmer et al., 2008). C76 inhibits HIF2α translation by binding to iron regulatory protein-1 that enables association with the IRE in the 5’UTR, even during hypoxia exposure. This association continuously represses HIF2α translation. C76 has shown promising results in both the prevention and treatment of pulmonary hypertension in rodent models (Dai et al., 2018) but demonstrates only micromolar potency in vitro , and is not orally bioavailable.
A series of highly selective, orally bioavailable HIF2α inhibitors with a favourable safety and tolerability profile have been developed, with reported efficacy in rodent cancer models and metastatic clear cell renal cell carcinoma (ccRCC) patients (Chen et al., 2016; Cho et al., 2016; Courtney et al., 2018; Wallace et al., 2016; Wehn et al., 2018). PT2567 has shown efficacy in rodent models of pulmonary hypertension (Hu et al., 2019).