Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials† †Electronic supplementary information (ESI) available: Synthetic procedures; supplementary methods including NMR, OGFOD1/Tpa1a/OFD1/PHD2/FIH hydroxylation assays, cell culture and immunoblotting, RT-qPCR assays and cell viability assays; supplementary figures; supplementary tables. See DOI: 10.1039/c7sc02103h

Autor: Yeh, Tzu-Lan, Leissing, Thomas M., Abboud, Martine I., Thinnes, Cyrille C., Atasoylu, Onur, Holt-Martyn, James P., Zhang, Dong, Tumber, Anthony, Lippl, Kerstin, Lohans, Christopher T., Leung, Ivanhoe K. H., Morcrette, Helen, Clifton, Ian J., Claridge, Timothy D. W., Kawamura, Akane, Flashman, Emily, Lu, Xin, Ratcliffe, Peter J., Chowdhury, Rasheduzzaman, Pugh, Christopher W., Schofield, Christopher J.
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Zdroj: Chemical Science
ISSN: 2041-6539
2041-6520
Popis: Four compounds in clinical trials for anaemia treatment are potent inhibitors of the hypoxia inducible factor (HIF) prolyl hydroxylases (PHDs), but differ in potency and how they interact with HIF at the PHD active site.
Inhibition of the human 2-oxoglutarate (2OG) dependent hypoxia inducible factor (HIF) prolyl hydroxylases (human PHD1–3) causes upregulation of HIF, thus promoting erythropoiesis and is therefore of therapeutic interest. We describe cellular, biophysical, and biochemical studies comparing four PHD inhibitors currently in clinical trials for anaemia treatment, that describe their mechanisms of action, potency against isolated enzymes and in cells, and selectivities versus representatives of other human 2OG oxygenase subfamilies. The ‘clinical’ PHD inhibitors are potent inhibitors of PHD catalyzed hydroxylation of the HIF-α oxygen dependent degradation domains (ODDs), and selective against most, but not all, representatives of other human 2OG dependent dioxygenase subfamilies. Crystallographic and NMR studies provide insights into the different active site binding modes of the inhibitors. Cell-based results reveal the inhibitors have similar effects on the upregulation of HIF target genes, but differ in the kinetics of their effects and in extent of inhibition of hydroxylation of the N- and C-terminal ODDs; the latter differences correlate with the biophysical observations.
Databáze: OpenAIRE
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