Pharmacological targeting of the HIF hydroxylases – A new field in medicine development

Chan, Mun Chiang; Holt‐Martyn, James P.; Schofield, Christopher J.; Ratcliffe, Peter J.

doi:10.1016/j.mam.2016.01.001

Cited by 118 publications

(132 citation statements)

References 206 publications

(309 reference statements)

Supporting

Mentioning

131

Contrasting

Unclassified

Order By: Relevance

“…Structures of the P317R, R371H and R396T variants with a clinically used inhibitor628 reveal similar overall folds to wt PHD2, that is, a modified double-stranded-β-helix (DSBH) core (β-strands I–VIII), supporting 2OG and His-X-Asp…His-mediated Fe(II) binding. The structures suggested that these variants probably manifest altered substrate binding (Fig.…”

Section: Resultsmentioning

confidence: 89%

“…As HIF target genes include those encoding for erythropoietin, vascular endothelial growth factor and many medicinally important proteins, therapeutic manipulation of the HIF system, in particular by PHD inhibition, is of interest. PHD inhibitors are in clinical trials for anaemia treatment via HIF-mediated erythropoietin upregulation67, although these inhibitors are not PHD isoform selective.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Structural basis for oxygen degradation domain selectivity of the HIF prolyl hydroxylases

et al. 2016

Self Cite

View full text Add to dashboard Cite

The response to hypoxia in animals involves the expression of multiple genes regulated by the αβ-hypoxia-inducible transcription factors (HIFs). The hypoxia-sensing mechanism involves oxygen limited hydroxylation of prolyl residues in the N- and C-terminal oxygen-dependent degradation domains (NODD and CODD) of HIFα isoforms, as catalysed by prolyl hydroxylases (PHD 1–3). Prolyl hydroxylation promotes binding of HIFα to the von Hippel–Lindau protein (VHL)–elongin B/C complex, thus signalling for proteosomal degradation of HIFα. We reveal that certain PHD2 variants linked to familial erythrocytosis and cancer are highly selective for CODD or NODD. Crystalline and solution state studies coupled to kinetic and cellular analyses reveal how wild-type and variant PHDs achieve ODD selectivity via different dynamic interactions involving loop and C-terminal regions. The results inform on how HIF target gene selectivity is achieved and will be of use in developing selective PHD inhibitors.

show abstract

Section: Resultsmentioning

confidence: 89%

mentioning

confidence: 99%

Structural basis for oxygen degradation domain selectivity of the HIF prolyl hydroxylases

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…Therefore, interfering with the HIF response may be a potential therapeutic approach for the control of immune-related disorders 13,129 . A number of pharmacological options for interference with the HIF pathway exist.…”

Section: Targeting the Hif Pathwaymentioning

confidence: 99%

Regulation of immunity and inflammation by hypoxia in immunological niches

2017

View full text Add to dashboard Cite

Immunological niches are focal sites of immune activity that can have varying microenvironmental features. Hypoxia is a feature of physiological and pathological immunological niches. The impact of hypoxia on immunity and inflammation can vary depending on the microenvironment and immune processes occurring in a given niche. In physiological immunological niches, such as the bone marrow, lymphoid tissue, placenta and intestinal mucosa, physiological hypoxia controls innate and adaptive immunity by modulating immune cell proliferation, development and effector function, largely via transcriptional changes driven by hypoxia-inducible factor (HIF). By contrast, in pathological immunological niches, such as tumours and chronically inflamed, infected or ischaemic tissues, pathological hypoxia can drive tissue dysfunction and disease development through immune cell dysregulation. Here, we differentiate between the effects of physiological and pathological hypoxia on immune cells and the consequences for immunity and inflammation in different immunological niches. Furthermore, we discuss the possibility of targeting hypoxia-sensitive pathways in immune cells for the treatment of inflammatory disease.

show abstract

“…Hydroxylase inhibitors have recently been entered into clinical trials for the promotion of erythropoiesis in models of chronic kidney disease-associated anemia (116)(117)(118). In these studies, the delivery of systemic doses of hydroxylase inhibitors was well tolerated by patients, paving the way for the possible use of these reagents for the treatment of inflammatory disorders and/or infectious disease.…”

Section: Clinical Potential Of Hydroxylase Inhibitorsmentioning

confidence: 99%