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Oral Abstract Presentations

Abstract 14: Small Molecule Inhibitors of the CD40-TRAF6 Interaction Reduce Atherosclerosis by Inducing Hypo-inflammatory Myeloid Cells

Tom Seijkens, Barbara Zarzycka, Oliver Soehnlein, Marten A. Hoeksema, Linda Beckers, Esther Smeets, Svenja U. Meiler, Marion J. Gijbels, Jochen Grommes, Roy Schrijver, Louis Boon, Tilman M. Hackeng, Gert Vriend, Sander B. Nabuurs, Norbert Gerdes, Menno P.J. de Winther, Christian Weber, Gerry A.F. Nicolaes, Esther Lutgens
Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;33:A14
Tom Seijkens
Department of Medical Biochemistry, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands
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Barbara Zarzycka
Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
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Oliver Soehnlein
Department of Pathology, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The NetherlandsInstitute for Cardiovascular Prevention (IPEK), Ludwig Maximilians University, Munich, Germany
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Marten A. Hoeksema
Department of Medical Biochemistry, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands
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Linda Beckers
Department of Medical Biochemistry, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands
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Esther Smeets
Department of Medical Biochemistry, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands
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Svenja U. Meiler
Department of Medical Biochemistry, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands
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Marion J. Gijbels
Department of Medical Biochemistry, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The NetherlandsDepartment of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The NetherlandsDepartment of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
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Jochen Grommes
European Vascular Center Aachen Maastricht, RWTH Aachen University Hospital, Aachen, Germany
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Roy Schrijver
Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
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Louis Boon
Bioceros BV, Utrecht, The Netherlands
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Tilman M. Hackeng
Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
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Gert Vriend
Centre for Molecular and Biomolecular Informatics (CMBI), Radboud University Medical Center, Nijmegen, The Netherlands
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Sander B. Nabuurs
Centre for Molecular and Biomolecular Informatics (CMBI), Radboud University Medical Center, Nijmegen, The NetherlandsLead Pharma Medicine, Nijmegen, The Netherlands
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Norbert Gerdes
Department of Medical Biochemistry, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The NetherlandsInstitute for Cardiovascular Prevention (IPEK), Ludwig Maximilians University, Munich, Germany
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Menno P.J. de Winther
Department of Medical Biochemistry, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands
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Christian Weber
Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilians University, Munich, GermanyGerman Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
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Gerry A.F. Nicolaes
Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
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Esther Lutgens
Department of Medical Biochemistry, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The NetherlandsInstitute for Cardiovascular Prevention (IPEK), Ludwig Maximilians University, Munich, Germany
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Abstract

The co-stimulatory CD40-CD40L dyad is well known for its pro-inflammatory role in atherosclerosis. Inhibition of CD40(L) in hyperlipidemic mice drastically reduces atherosclerosis. However, long term inhibition of CD40(L) results in immunosuppression and/or thromboembolic events. Therefore more targeted inhibition of the CD40L-CD40 dyad is required. To elicit intracellular signalling upon activation, CD40 needs to recruit adaptor proteins: the tumour necrosis factor receptor-associated factors (TRAFs). Using mice with a mutation in the CD40-TRAF binding site, we previously showed that CD40-TRAF6, and not CD40-TRAF2/3/5, are pivotal in atherosclerosis.

To discover small drug-like molecules that inhibit the CD40-TRAF6 interaction an in silico approach of virtual ligand screening was used; this resulted in the identification of 40.000 compounds. Analysis of the top 800 compounds identified 7 compounds that dose-dependently reduced NFκB activation and IL1β and IL6 expression in RAW cells and CD40-stimulated bone marrow-derived macrophages, respectively. Surface plasmon resonance experiments confirmed direct binding of the compounds to the TRAF6 C-domain.

To analyze the effects of the top two compounds on atherosclerosis, Apoe-/- mice were daily treated with compounds 6877002 or 6860766 for 6 weeks. Compound treatment reduced atherosclerosis in the aortic arch by 47.1% (6877002) and 66.8% (6860766). The number of plaque monocytes/macrophages was decreased by 41.4% (6877002) and 53.0% (6860766), and granulocytes by 62.5% (6877002) and 41.5% (6860766). Intravital microscopy showed that the compounds reduced monocyte recruitment to the endothelium by 40.1% (6877002) and 51.2% (6860766), neutrophil adhesion was reduced by 40.2% (6877002) and 51.2% (6860766). In accordance, expression of CCL2-CCR2 and CCL5-CCR5 was remarkably reduced in compound treated macrophages. Moreover, compound treatment abolished CD40-induced expression of TNFα, IL1β, IL6, IL10, and IL12.

These results establish the importance and possibilities of long-term therapeutic inhibition of CD40-TRAF6 interactions in atherosclerosis and other inflammatory diseases and harbor the potential to overcome the current limitations of CD40(L) blocking therapies.

  • CD40-TRAF6
  • small molecule inhibitors
  • © 2013 by American Heart Association, Inc.
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April 2018, Volume 38, Issue 4
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    Abstract 14: Small Molecule Inhibitors of the CD40-TRAF6 Interaction Reduce Atherosclerosis by Inducing Hypo-inflammatory Myeloid Cells
    Tom Seijkens, Barbara Zarzycka, Oliver Soehnlein, Marten A. Hoeksema, Linda Beckers, Esther Smeets, Svenja U. Meiler, Marion J. Gijbels, Jochen Grommes, Roy Schrijver, Louis Boon, Tilman M. Hackeng, Gert Vriend, Sander B. Nabuurs, Norbert Gerdes, Menno P.J. de Winther, Christian Weber, Gerry A.F. Nicolaes and Esther Lutgens
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;33:A14, originally published October 20, 2015

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    Abstract 14: Small Molecule Inhibitors of the CD40-TRAF6 Interaction Reduce Atherosclerosis by Inducing Hypo-inflammatory Myeloid Cells
    Tom Seijkens, Barbara Zarzycka, Oliver Soehnlein, Marten A. Hoeksema, Linda Beckers, Esther Smeets, Svenja U. Meiler, Marion J. Gijbels, Jochen Grommes, Roy Schrijver, Louis Boon, Tilman M. Hackeng, Gert Vriend, Sander B. Nabuurs, Norbert Gerdes, Menno P.J. de Winther, Christian Weber, Gerry A.F. Nicolaes and Esther Lutgens
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;33:A14, originally published October 20, 2015
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