title: Selective small molecule probes for the hypoxia inducible factor (HIF) prolyl hydroxylases.
abstract: The hypoxia inducible factor (HIF) system is central to the signaling of low oxygen (hypoxia) in animals. The levels of HIF-α isoforms are regulated in an oxygen-dependent manner by the activity of the HIF prolyl-hydroxylases (PHD or EGLN enzymes), which are Fe(II) and 2-oxoglutarate (2OG) dependent oxygenases. Here, we describe biochemical, crystallographic, cellular profiling, and animal studies on PHD inhibitors including selectivity studies using a representative set of human 2OG oxygenases. We identify suitable probe compounds for use in studies on the functional effects of PHD inhibition in cells and in animals.
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford , Mansfield Road, Oxford, OX1 3TA, United Kingdom.
authors.forename: Rasheduzzaman
authors.initials: R
authors.lastname: Chowdhury
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Candela-Lena
authors.forename: Mun Chiang
authors.initials: MC
authors.lastname: Chan
authors.forename: David Jeremy
authors.initials: DJ
authors.lastname: Greenald
authors.forename: Kar Kheng
authors.initials: KK
authors.lastname: Yeoh
authors.forename: Ya-Min
authors.initials: YM
authors.lastname: Tian
authors.forename: Michael A
authors.initials: MA
authors.lastname: McDonough
authors.forename: Anthony
authors.initials: A
authors.lastname: Tumber
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Rose
authors.forename: Ana
authors.initials: A
authors.lastname: Conejo-Garcia
authors.forename: Marina
authors.initials: M
authors.lastname: Demetriades
authors.forename: Sinnakaruppan
authors.initials: S
authors.lastname: Mathavan
authors.forename: Akane
authors.initials: A
authors.lastname: Kawamura
authors.forename: Myung Kyu
authors.initials: MK
authors.lastname: Lee
authors.forename: Freek
authors.initials: F
authors.lastname: van Eeden
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Pugh
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ratcliffe
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schofield
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001681:Biological Assay; D002460:Cell Line; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: C497442:HIF1A protein, human; D006571:Heterocyclic Compounds; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D054852:Small Molecule Libraries; C490190:EGLN1 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases