Dual-action inhibitors of HIF prolyl hydroxylases that induce binding of a second iron ion = 두번째 철이온의 결합을 유도하는 HIF 플로린 수산화효소의 이중활성 억제제들

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Title
Dual-action inhibitors of HIF prolyl hydroxylases that induce binding of a second iron ion = 두번째 철이온의 결합을 유도하는 HIF 플로린 수산화효소의 이중활성 억제제들
Author(s)
K K Yeoh; M C Chan; A Thalhammer; M Demetriades; R Chowdhury; Y M Tian; I Stolze; L A McNeill; Myung Kyu Lee; E C Y Woon; M M Mackeen; A Kawamura; P J Ratcliffe; J Mecinovic; C J Schofield
Bibliographic Citation
Organic & Biomolecular Chemistry, vol. 11, no. 5, pp. 732-745
Publication Year
2013
Abstract
Inhibition of the hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD or EGLN enzymes) is of interest for the treatment of anemia and ischemia-related diseases. Most PHD inhibitors work by binding to the single ferrous ion and competing with 2-oxoglutarate (2OG) co-substrate for binding at the PHD active site. Non-specific iron chelators also inhibit the PHDs, both in vitro and in cells. We report the identification of dual action PHD inhibitors, which bind to the active site iron and also induce the binding of a second iron ion at the active site. Following analysis of small-molecule iron complexes and application of non-denaturing protein mass spectrometry to assess PHD2·iron· inhibitor stoichiometry, selected diacylhydrazines were identified as PHD2 inhibitors that induce the binding of a second iron ion. Some compounds were shown to inhibit the HIF hydroxylases in human hepatoma and renal carcinoma cell lines.
ISSN
1477-0520
Publisher
Royal Soc Chem
DOI
http://dx.doi.org/10.1039/c2ob26648b
Type
Article
Appears in Collections:
Division of Biomaterials Research > Bionanotechnology Research Center > 1. Journal Articles
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