Dual-action inhibitors of HIF prolyl hydroxylases that induce binding of a second iron ion

Kar Kheng Yeoh, Mun Chiang Chan, Armin Thalhammer, Marina Demetriades, Rasheduzzaman Chowdhury, Ya Min Tian, Ineke Stolze, Luke A. McNeill, Myung Kyu Lee, Esther C Y Woon, Muhammad Mukram Mohamed Mackeen, Akane Kawamura, Peter J. Ratcliffe, Jasmin Mecinović, Christopher J. Schofield

Research output: Contribution to journalArticle

15 Citations (Scopus)

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. This journal is

Original languageEnglish
Pages (from-to)732-745
Number of pages14
JournalOrganic and Biomolecular Chemistry
Volume11
Issue number5
DOIs
Publication statusPublished - 7 Feb 2013

Fingerprint

Prolyl Hydroxylases
hypoxia
inhibitors
Iron
Ions
iron
Catalytic Domain
ions
anemias
ischemia
Chelating Agents
Mixed Function Oxygenases
cultured cells
Stoichiometry
Mass spectrometry
enzymes
Anemia
stoichiometry
Hepatocellular Carcinoma
Mass Spectrometry

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Biochemistry

Cite this

Yeoh, K. K., Chan, M. C., Thalhammer, A., Demetriades, M., Chowdhury, R., Tian, Y. M., ... Schofield, C. J. (2013). Dual-action inhibitors of HIF prolyl hydroxylases that induce binding of a second iron ion. Organic and Biomolecular Chemistry, 11(5), 732-745. https://doi.org/10.1039/c2ob26648b

Dual-action inhibitors of HIF prolyl hydroxylases that induce binding of a second iron ion. / Yeoh, Kar Kheng; Chan, Mun Chiang; Thalhammer, Armin; Demetriades, Marina; Chowdhury, Rasheduzzaman; Tian, Ya Min; Stolze, Ineke; McNeill, Luke A.; Lee, Myung Kyu; Woon, Esther C Y; Mohamed Mackeen, Muhammad Mukram; Kawamura, Akane; Ratcliffe, Peter J.; Mecinović, Jasmin; Schofield, Christopher J.

In: Organic and Biomolecular Chemistry, Vol. 11, No. 5, 07.02.2013, p. 732-745.

Research output: Contribution to journalArticle

Yeoh, KK, Chan, MC, Thalhammer, A, Demetriades, M, Chowdhury, R, Tian, YM, Stolze, I, McNeill, LA, Lee, MK, Woon, ECY, Mohamed Mackeen, MM, Kawamura, A, Ratcliffe, PJ, Mecinović, J & Schofield, CJ 2013, 'Dual-action inhibitors of HIF prolyl hydroxylases that induce binding of a second iron ion', Organic and Biomolecular Chemistry, vol. 11, no. 5, pp. 732-745. https://doi.org/10.1039/c2ob26648b
Yeoh, Kar Kheng ; Chan, Mun Chiang ; Thalhammer, Armin ; Demetriades, Marina ; Chowdhury, Rasheduzzaman ; Tian, Ya Min ; Stolze, Ineke ; McNeill, Luke A. ; Lee, Myung Kyu ; Woon, Esther C Y ; Mohamed Mackeen, Muhammad Mukram ; Kawamura, Akane ; Ratcliffe, Peter J. ; Mecinović, Jasmin ; Schofield, Christopher J. / Dual-action inhibitors of HIF prolyl hydroxylases that induce binding of a second iron ion. In: Organic and Biomolecular Chemistry. 2013 ; Vol. 11, No. 5. pp. 732-745.
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