Roxadustat, the company's most advanced product candidate, is an oral small molecule inhibitor of HIF prolyl hydroxylase
Liu, "Induction of erythropoiesis by hypoxia-inducible factor prolyl hydroxylase
inhibitors without promotion of tumor initiation, progression, or metastasis in a VEGF-sensitive model of spontaneous breast cancer," Hypoxia, vol.
These include hypoxia-inducible factor 2 alpha (HIF2A), fumarate hydratase (FH), prolyl hydroxylase
types 1 and 2 (PHD1 and PHD2), Harvey rat sarcoma viral oncogene homolog (HRAS), kinesin family member 1B (KIF1B), and X-linked alpha thalassemia mental retardation (ATRX) genes [16-20].
ALK: RNA and DNA demethylase family; JMJ: jumonji histone demethylases; TET: ten-eleven translocation DNA demethylases; OGFO: 2-oxoglutarate- and [Fe.sup.2+]- dependent oxygenase; PLOD: procollagen-lysine_[alpha]-KG_5-dioxygenases; P3H: collagen prolyl 3- hydroxylase; P4H: collagen prolyl 4- hydroxylases; BBOX1: [gamma]-butyrobetaine dioxygenases; DBH: dopamine beta-monooxygenase; PHD: HIF- prolyl hydroxylase
; FIH: factor inhibiting HIF.
Under normal oxygen conditions, HIF proteins are low, their levels regulated by an enzyme called prolyl hydroxylase
. This enzyme is inactivated under hypoxic conditions, or in the presence of reactive oxygen species.
Cell-free collagen synthesis on membrane-bound polysomes of chick embryo connective tissue and the localization of prolyl hydroxylase
on the polysome-membrane complex.
This interaction is significant because OS-9 has also been shown to interact with HIF-1[alpha] and prolyl hydroxylase
, proteins which mediate the cell's response to changes in oxygen concentration.
Under normoxia, specific prolyl hydroxylase
domain containing enzymes (PHD 1, 2, and 3) use molecular oxygen to immediately hydroxylate distinct prolyl residues of newly synthesized HIF-[alpha]-subunits.
KSHV induces the expression of miRNA clusters that inhibit the expression of gene, encoding the HIF1A prolyl hydroxylase
PHD1 and also the mitochondrial heat shock protein HSPA9 .
HIF-1 is a transcription factor and a heterodimer composed of two subunits: HIF-1a and HIF-1b (aryl hydrocarbon receptor nuclear translocator), whose pathway is targeted to control angiogenesis via the silencing of prolyl hydroxylase
domain-containing protein 2 (PHD2) [1, 18].
This orally administered small molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase
(HIF-PHI), is among the most clinically advanced candidate in this new class of potential anemia therapies.
Vitamin C is the cofactor for enzymes like lysyl hydroxylase and prolyl hydroxylase
, enzymes that are very important for making hydroxylysine and hydroxyproline, which play a crucial role in the stability of the structure of collagen triple helix.