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).