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Research ArticleArticle

Inhibition of Human Sterol Δ7-Reductase and Other Postlanosterol Enzymes by LK-980, a Novel Inhibitor of Cholesterol Synthesis

Jure Ačimovič, Tina Korošec, Matej Seliškar, Ingemar Bjorkhem, Katalin Monostory, Pal Szabo, Jean-Marc Pascussi, Ales Belič, Uroš Urleb, Darko Kocjan and Damjana Rozman
Drug Metabolism and Disposition January 2011, 39 (1) 39-46; DOI: https://doi.org/10.1124/dmd.110.035840
Jure Ačimovič
Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (J.A., D.R.); Lek Pharmaceuticals d.d., Drug Discovery, Ljubljana, Slovenia (T.K., M.S., U.U.); Division of Clinical Chemistry, Karolinska Institutet, Division of Clinical Chemistry, Stockholm, Huddinge, Sweden (I.B.); Chemical Research Center, Hungarian Academy of Sciences, Budapest, Hungary (K.M., P.S.); Institute of Functional Genomics, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203 and Institut National de la Santé et de la Recherche Médicale U661, University Montpellier 1 and 2, Montpellier, France (J.-M.P.), Faculty of Electrical Engineering, University of Ljubljana, Ljubljana, Slovenia (A.B.); and L14 Laboratory for Biomolecular Structure, National Institute of Chemistry, EN→FIST Center of Excellence, Ljubljana, Slovenia (D.K.)
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Tina Korošec
Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (J.A., D.R.); Lek Pharmaceuticals d.d., Drug Discovery, Ljubljana, Slovenia (T.K., M.S., U.U.); Division of Clinical Chemistry, Karolinska Institutet, Division of Clinical Chemistry, Stockholm, Huddinge, Sweden (I.B.); Chemical Research Center, Hungarian Academy of Sciences, Budapest, Hungary (K.M., P.S.); Institute of Functional Genomics, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203 and Institut National de la Santé et de la Recherche Médicale U661, University Montpellier 1 and 2, Montpellier, France (J.-M.P.), Faculty of Electrical Engineering, University of Ljubljana, Ljubljana, Slovenia (A.B.); and L14 Laboratory for Biomolecular Structure, National Institute of Chemistry, EN→FIST Center of Excellence, Ljubljana, Slovenia (D.K.)
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Matej Seliškar
Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (J.A., D.R.); Lek Pharmaceuticals d.d., Drug Discovery, Ljubljana, Slovenia (T.K., M.S., U.U.); Division of Clinical Chemistry, Karolinska Institutet, Division of Clinical Chemistry, Stockholm, Huddinge, Sweden (I.B.); Chemical Research Center, Hungarian Academy of Sciences, Budapest, Hungary (K.M., P.S.); Institute of Functional Genomics, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203 and Institut National de la Santé et de la Recherche Médicale U661, University Montpellier 1 and 2, Montpellier, France (J.-M.P.), Faculty of Electrical Engineering, University of Ljubljana, Ljubljana, Slovenia (A.B.); and L14 Laboratory for Biomolecular Structure, National Institute of Chemistry, EN→FIST Center of Excellence, Ljubljana, Slovenia (D.K.)
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Ingemar Bjorkhem
Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (J.A., D.R.); Lek Pharmaceuticals d.d., Drug Discovery, Ljubljana, Slovenia (T.K., M.S., U.U.); Division of Clinical Chemistry, Karolinska Institutet, Division of Clinical Chemistry, Stockholm, Huddinge, Sweden (I.B.); Chemical Research Center, Hungarian Academy of Sciences, Budapest, Hungary (K.M., P.S.); Institute of Functional Genomics, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203 and Institut National de la Santé et de la Recherche Médicale U661, University Montpellier 1 and 2, Montpellier, France (J.-M.P.), Faculty of Electrical Engineering, University of Ljubljana, Ljubljana, Slovenia (A.B.); and L14 Laboratory for Biomolecular Structure, National Institute of Chemistry, EN→FIST Center of Excellence, Ljubljana, Slovenia (D.K.)
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Katalin Monostory
Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (J.A., D.R.); Lek Pharmaceuticals d.d., Drug Discovery, Ljubljana, Slovenia (T.K., M.S., U.U.); Division of Clinical Chemistry, Karolinska Institutet, Division of Clinical Chemistry, Stockholm, Huddinge, Sweden (I.B.); Chemical Research Center, Hungarian Academy of Sciences, Budapest, Hungary (K.M., P.S.); Institute of Functional Genomics, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203 and Institut National de la Santé et de la Recherche Médicale U661, University Montpellier 1 and 2, Montpellier, France (J.-M.P.), Faculty of Electrical Engineering, University of Ljubljana, Ljubljana, Slovenia (A.B.); and L14 Laboratory for Biomolecular Structure, National Institute of Chemistry, EN→FIST Center of Excellence, Ljubljana, Slovenia (D.K.)
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Pal Szabo
Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (J.A., D.R.); Lek Pharmaceuticals d.d., Drug Discovery, Ljubljana, Slovenia (T.K., M.S., U.U.); Division of Clinical Chemistry, Karolinska Institutet, Division of Clinical Chemistry, Stockholm, Huddinge, Sweden (I.B.); Chemical Research Center, Hungarian Academy of Sciences, Budapest, Hungary (K.M., P.S.); Institute of Functional Genomics, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203 and Institut National de la Santé et de la Recherche Médicale U661, University Montpellier 1 and 2, Montpellier, France (J.-M.P.), Faculty of Electrical Engineering, University of Ljubljana, Ljubljana, Slovenia (A.B.); and L14 Laboratory for Biomolecular Structure, National Institute of Chemistry, EN→FIST Center of Excellence, Ljubljana, Slovenia (D.K.)
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Jean-Marc Pascussi
Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (J.A., D.R.); Lek Pharmaceuticals d.d., Drug Discovery, Ljubljana, Slovenia (T.K., M.S., U.U.); Division of Clinical Chemistry, Karolinska Institutet, Division of Clinical Chemistry, Stockholm, Huddinge, Sweden (I.B.); Chemical Research Center, Hungarian Academy of Sciences, Budapest, Hungary (K.M., P.S.); Institute of Functional Genomics, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203 and Institut National de la Santé et de la Recherche Médicale U661, University Montpellier 1 and 2, Montpellier, France (J.-M.P.), Faculty of Electrical Engineering, University of Ljubljana, Ljubljana, Slovenia (A.B.); and L14 Laboratory for Biomolecular Structure, National Institute of Chemistry, EN→FIST Center of Excellence, Ljubljana, Slovenia (D.K.)
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Ales Belič
Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (J.A., D.R.); Lek Pharmaceuticals d.d., Drug Discovery, Ljubljana, Slovenia (T.K., M.S., U.U.); Division of Clinical Chemistry, Karolinska Institutet, Division of Clinical Chemistry, Stockholm, Huddinge, Sweden (I.B.); Chemical Research Center, Hungarian Academy of Sciences, Budapest, Hungary (K.M., P.S.); Institute of Functional Genomics, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203 and Institut National de la Santé et de la Recherche Médicale U661, University Montpellier 1 and 2, Montpellier, France (J.-M.P.), Faculty of Electrical Engineering, University of Ljubljana, Ljubljana, Slovenia (A.B.); and L14 Laboratory for Biomolecular Structure, National Institute of Chemistry, EN→FIST Center of Excellence, Ljubljana, Slovenia (D.K.)
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Uroš Urleb
Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (J.A., D.R.); Lek Pharmaceuticals d.d., Drug Discovery, Ljubljana, Slovenia (T.K., M.S., U.U.); Division of Clinical Chemistry, Karolinska Institutet, Division of Clinical Chemistry, Stockholm, Huddinge, Sweden (I.B.); Chemical Research Center, Hungarian Academy of Sciences, Budapest, Hungary (K.M., P.S.); Institute of Functional Genomics, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203 and Institut National de la Santé et de la Recherche Médicale U661, University Montpellier 1 and 2, Montpellier, France (J.-M.P.), Faculty of Electrical Engineering, University of Ljubljana, Ljubljana, Slovenia (A.B.); and L14 Laboratory for Biomolecular Structure, National Institute of Chemistry, EN→FIST Center of Excellence, Ljubljana, Slovenia (D.K.)
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Darko Kocjan
Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (J.A., D.R.); Lek Pharmaceuticals d.d., Drug Discovery, Ljubljana, Slovenia (T.K., M.S., U.U.); Division of Clinical Chemistry, Karolinska Institutet, Division of Clinical Chemistry, Stockholm, Huddinge, Sweden (I.B.); Chemical Research Center, Hungarian Academy of Sciences, Budapest, Hungary (K.M., P.S.); Institute of Functional Genomics, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203 and Institut National de la Santé et de la Recherche Médicale U661, University Montpellier 1 and 2, Montpellier, France (J.-M.P.), Faculty of Electrical Engineering, University of Ljubljana, Ljubljana, Slovenia (A.B.); and L14 Laboratory for Biomolecular Structure, National Institute of Chemistry, EN→FIST Center of Excellence, Ljubljana, Slovenia (D.K.)
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Damjana Rozman
Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (J.A., D.R.); Lek Pharmaceuticals d.d., Drug Discovery, Ljubljana, Slovenia (T.K., M.S., U.U.); Division of Clinical Chemistry, Karolinska Institutet, Division of Clinical Chemistry, Stockholm, Huddinge, Sweden (I.B.); Chemical Research Center, Hungarian Academy of Sciences, Budapest, Hungary (K.M., P.S.); Institute of Functional Genomics, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203 and Institut National de la Santé et de la Recherche Médicale U661, University Montpellier 1 and 2, Montpellier, France (J.-M.P.), Faculty of Electrical Engineering, University of Ljubljana, Ljubljana, Slovenia (A.B.); and L14 Laboratory for Biomolecular Structure, National Institute of Chemistry, EN→FIST Center of Excellence, Ljubljana, Slovenia (D.K.)
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Abstract

Novel potential inhibitors of the postsqualene portion of cholesterol synthesis were screened in HepG2 cells. 2-(4-Phenethylpiperazin-1-yl)-1-(pyridine-3-yl)ethanol (LK-980) was identified as a prospective compound and was characterized further in cultures of human primary hepatocytes from seven donors. In vitro kinetic measurements show that the half-life of LK-980 is at least 4.3 h. LK-980 does not induce CYP3A4 mRNA nor enzyme activity. Target prediction was performed by gas chromatography-mass spectrometry, allowing simultaneous separation and quantification of nine late cholesterol intermediates. Experiments indicated that human sterol Δ7-reductase (DHCR7) is the major target of LK-980 (34-fold increase of 7-dehydrocholesterol), whereas human sterol Δ14-reductase (DHCR14), human sterol Δ24-reductase (DHCR24), and human sterol C5-desaturase (SC5DL) represent minor targets. In the absence of purified enzymes, we used the mathematical model of cholesterol synthesis to evaluate whether indeed more than a single enzyme is inhibited. In silico inhibition of only DHCR7 modifies the flux of cholesterol intermediates, resulting in a sterol profile that does not support experimental data. Partial inhibition of the DHCR14, DHCR24, and SC5DL steps, in addition to DHCR7, supports the experimental sterol profile. In conclusion, we provide experimental and computational evidence that LK-980, a novel inhibitor from the late portion of cholesterol synthesis, inhibits primarily DHCR7 and to a lesser extent three other enzymes from this pathway.

Footnotes

    • Received August 12, 2010.
    • Accepted October 13, 2010.
  • This work was supported by the European Community [Grant LSHG-CT-2005-512096, STEROLTALK]; the Slovenian-Hungarian Intergovernmental S&T Cooperation Programme [Grant Sl-5/2008]; and the Research Agency of the Republic Slovenia [Grants J1-9438, P1-0104].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.035840.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    HMGCR
    HMG-CoA reductase
    DHCR14
    human sterol Δ14-reductase
    FF-MAS
    follicular fluid meiosis activating sterol (4,4-dimethyl-5a-cholesta-8,14,24-triene-3b-ol)
    T-MAS
    testis meiosis activating sterol(4,4-dimethyl-5a-cholesta-8,24-diene-3b-ol)
    DHCR24
    human sterol Δ24-reductase
    DHCR7
    human sterol Δ7-reductase
    SC5DL
    human sterol C5-desaturase
    LK-980
    2-(4-phenethylpiperazin-1-yl)-1-(pyridine-3-yl)ethanol
    GC
    gas chromatography
    MS
    mass spectrometry
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    RT
    reverse transcriptase
    PCR
    polymerase chain reaction
    LSD
    least significant difference
    Ay 9944
    trans-1,4-bis(2-chlorobenzaminomethyl) cyclohexane dihydrochloride
    SR 31747
    N-cyclohexyl-N-ethyl-3-(3-chloro-4-cyclohexylphenyl)propen-2-ylamine hydrochloride
    SKF 104976
    3β-hydroxylanost-8,15-dien-32-carboxylic acid
    CYP51A1
    lanosterol 14α-demethylase
    MER-29
    triparanol
    LK-935
    2-((3,4-dichlorophenethyl)(propyl)amino)-1-(pyridin-3-yl)ethanol.

  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (1)
Drug Metabolism and Disposition
Vol. 39, Issue 1
1 Jan 2011
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Research ArticleArticle

Inhibition of Human Sterol Δ7-Reductase and Other Postlanosterol Enzymes by LK-980, a Novel Inhibitor of Cholesterol Synthesis

Jure Ačimovič, Tina Korošec, Matej Seliškar, Ingemar Bjorkhem, Katalin Monostory, Pal Szabo, Jean-Marc Pascussi, Ales Belič, Uroš Urleb, Darko Kocjan and Damjana Rozman
Drug Metabolism and Disposition January 1, 2011, 39 (1) 39-46; DOI: https://doi.org/10.1124/dmd.110.035840

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Research ArticleArticle

Inhibition of Human Sterol Δ7-Reductase and Other Postlanosterol Enzymes by LK-980, a Novel Inhibitor of Cholesterol Synthesis

Jure Ačimovič, Tina Korošec, Matej Seliškar, Ingemar Bjorkhem, Katalin Monostory, Pal Szabo, Jean-Marc Pascussi, Ales Belič, Uroš Urleb, Darko Kocjan and Damjana Rozman
Drug Metabolism and Disposition January 1, 2011, 39 (1) 39-46; DOI: https://doi.org/10.1124/dmd.110.035840
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