Hypoxia inducible factors (HIFs) are master regulators of the hypoxia response. HIFs are heterodimers consisting of an a and a ß subunit. HIF1a /HIF1ß and HIF2a HIF1ß dimers are primary factors regulating hypoxic transcriptional responses in most mammalian cells. HIF1 plays dominant role in the response to acute hypoxia, whereas HIF2 drives the response to chronic hypoxia. Both HIF1 and HIF2 levels in cells are directly regulated by four oxygen-sensitive hydroxylases: 3 prolyl hydroxylases (PHD1-3) and 1 asparaginyl hydroxylase, factor inhibiting HIF (FIH). In normoxia, hydroxylation of either of two prolyl residues in the oxygen dependent degradation domains (ODDDs) of HIFa subunit promotes its interaction with the von Hippel-Lindau ubiqutin E3 ligase complex. Thereafter, HIFa subunit is targeted for ubiquitination, and subsequent proteosomal degradation. In addition, asparaginyl hydroxylation prevents binding of HIF to its coactivator proteins thus inhibiting HIF mediated transcription. In hypoxia, the activity of the HIF hydroxylases is reduced, and levels of transcriptionally active HIF rise causing induction of a gene array that contributes to cell protection, as well as upregulating expression of genes leading to apoptosis. The specific set of gene upregulation upon HIF activation is depended on the context and cell types. Owing to the direct connection between hydroxylase-dependent catalysis and the physiological response to hypoxia, the modulation of HIF hydroxylase activity is of potential therapeutic use in a range of disease states including anaemia and ischaemic diseases. A number of chemicals with a similar structure to 2 oxoglutarate (2OG), a substrate of hydroxylase, have been synthesized. These chemicals compete with 2OG for the binding site of HIF hydroxylases and inhibit their activities, thus leading to HIF stabilisation. Four HIF hydroxylase inhibitors have progressed to Phase II or III clinical trials for treating anaemia in patients with chronic kidney disease (CKD). The use of small molecule HIF hydroxylase inhibitors has many advantages such as low price, good compliance, and few allergic reactions. It is important to develop high potent and selective PHD inhibitors for clinical uses, because of the pleiotropic and contrast nature of the hypoxic response and large number of components involved, and the fact that there are ~60 other human 2OG oxygenases some of which play roles in the hypoxic response. The focus of this Research Topic will be on the current development of hypoxia mimetic agents for clinical uses. We will cover a wide range of approaches and topics to highlight the state of the art, the limitations, and the promises in the field, which will be of interest to a broad community of researchers engaged in drug discovery.
Hypoxia inducible factors (HIFs) are master regulators of the hypoxia response. HIFs are heterodimers consisting of an a and a ß subunit. HIF1a /HIF1ß and HIF2a HIF1ß dimers are primary factors regulating hypoxic transcriptional responses in most mammalian cells. HIF1 plays dominant role in the response to acute hypoxia, whereas HIF2 drives the response to chronic hypoxia. Both HIF1 and HIF2 levels in cells are directly regulated by four oxygen-sensitive hydroxylases: 3 prolyl hydroxylases (PHD1-3) and 1 asparaginyl hydroxylase, factor inhibiting HIF (FIH). In normoxia, hydroxylation of either of two prolyl residues in the oxygen dependent degradation domains (ODDDs) of HIFa subunit promotes its interaction with the von Hippel-Lindau ubiqutin E3 ligase complex. Thereafter, HIFa subunit is targeted for ubiquitination, and subsequent proteosomal degradation. In addition, asparaginyl hydroxylation prevents binding of HIF to its coactivator proteins thus inhibiting HIF mediated transcription. In hypoxia, the activity of the HIF hydroxylases is reduced, and levels of transcriptionally active HIF rise causing induction of a gene array that contributes to cell protection, as well as upregulating expression of genes leading to apoptosis. The specific set of gene upregulation upon HIF activation is depended on the context and cell types. Owing to the direct connection between hydroxylase-dependent catalysis and the physiological response to hypoxia, the modulation of HIF hydroxylase activity is of potential therapeutic use in a range of disease states including anaemia and ischaemic diseases. A number of chemicals with a similar structure to 2 oxoglutarate (2OG), a substrate of hydroxylase, have been synthesized. These chemicals compete with 2OG for the binding site of HIF hydroxylases and inhibit their activities, thus leading to HIF stabilisation. Four HIF hydroxylase inhibitors have progressed to Phase II or III clinical trials for treating anaemia in patients with chronic kidney disease (CKD). The use of small molecule HIF hydroxylase inhibitors has many advantages such as low price, good compliance, and few allergic reactions. It is important to develop high potent and selective PHD inhibitors for clinical uses, because of the pleiotropic and contrast nature of the hypoxic response and large number of components involved, and the fact that there are ~60 other human 2OG oxygenases some of which play roles in the hypoxic response. The focus of this Research Topic will be on the current development of hypoxia mimetic agents for clinical uses. We will cover a wide range of approaches and topics to highlight the state of the art, the limitations, and the promises in the field, which will be of interest to a broad community of researchers engaged in drug discovery.
