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Biochem Biophys Res Commun. 2016 Apr 1;472(2):313-8. doi: 10.1016/j.bbrc.2016.02.115. Epub 2016 Mar 3.

Pyrithione Zn selectively inhibits hypoxia-inducible factor prolyl hydroxylase PHD3.

Author information

1
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.
2
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.
3
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.
4
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.

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.

KEYWORDS:

Hypoxia-inducible factor; Isoform selective inhibitor; Prolyl hydroxylase; Pyrithione Zn

PMID:
26940742
DOI:
10.1016/j.bbrc.2016.02.115
[Indexed for MEDLINE]

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