title: Pyrithione Zn selectively inhibits hypoxia-inducible factor prolyl hydroxylase PHD3.
abstract: Increasing evidence emphasizes the role of the hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) isoforms in regulating non-HIF substrates, but isoform selective PHD inhibitors under physiological conditions have not yet been reported. Here we have identified pyrithione Zn (PZ) as a potent, isoform-selective PHD3 inhibitor. The IC50 value of PZ was determined as 0.98 μM for PHD3, while it did not show any inhibitory activity toward full length and truncated PHD2 up to 1 mM. The selective efficacy of PZ was further demonstrated at the cellular level by observing inhibition of the PHD3-dependent DNA damage response pathway without stabilization of HIF-1α.
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.
authors.forename: Yu-Ran
authors.initials: YR
authors.lastname: Na
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea; Department of Biological Chemistry, Korea University of Science and Technology (UST), KIST Campus, Seoul 02792, Republic of Korea.
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Woo
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea; Department of Biomedical Engineering, Korea University of Science and Technology (UST), KIST Campus, Seoul 02792, Republic of Korea. Electronic address: soyeonkim@kist.re.kr.
authors.forename: So Yeon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea; Department of Biological Chemistry, Korea University of Science and Technology (UST), KIST Campus, Seoul 02792, Republic of Korea. Electronic address: eunyang@kist.re.kr.
authors.forename: Eun Gyeong
authors.initials: EG
authors.lastname: Yang
mesh_terms: D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009942:Organometallic Compounds / Q000008:administration & dosage* / Q000737:chemistry*; D011725:Pyridines / Q000008:administration & dosage* / Q000737:chemistry*
chemical_list: D009942:Organometallic Compounds; D011725:Pyridines; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; C010423:pyrithione zinc
keywords: Hypoxia-inducible factor; Isoform selective inhibitor; Prolyl hydroxylase; Pyrithione Zn