title: Dual-action inhibitors of HIF prolyl hydroxylases that induce binding of a second iron ion.
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.
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
authors.forename: Kar Kheng
authors.initials: KK
authors.lastname: Yeoh
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
authors.forename: Mun Chiang
authors.initials: MC
authors.lastname: Chan
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
authors.forename: Armin
authors.initials: A
authors.lastname: Thalhammer
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
authors.forename: Marina
authors.initials: M
authors.lastname: Demetriades
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
authors.forename: Rasheduzzaman
authors.initials: R
authors.lastname: Chowdhury
authors.affiliation: Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, United Kingdom.
authors.forename: Ya-Min
authors.initials: YM
authors.lastname: Tian
authors.affiliation: Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, United Kingdom.
authors.forename: Ineke
authors.initials: I
authors.lastname: Stolze
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
authors.forename: Luke A
authors.initials: LA
authors.lastname: McNeill
authors.affiliation: BioNanotechnology Research Centre, Korea Institute of Bioscience & Biotechnology, Yuseong 305-333, Daejeon, Korea.
authors.forename: Myung Kyu
authors.initials: MK
authors.lastname: Lee
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
authors.forename: Esther C Y
authors.initials: ECY
authors.lastname: Woon
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
authors.forename: Mukram M
authors.initials: MM
authors.lastname: Mackeen
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
authors.forename: Akane
authors.initials: A
authors.lastname: Kawamura
authors.affiliation: Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ratcliffe
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Mecinović
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schofield
mesh_terms: D020134:Catalytic Domain; D045744:Cell Line, Tumor; D006801:Humans; D006834:Hydrazines / Q000737:chemistry* / Q000494:pharmacology*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007501:Iron / Q000378:metabolism*; D062105:Molecular Docking Simulation; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D006834:Hydrazines; D007501:Iron; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases