title: Identification of Potential Off-target Toxicity Liabilities of Catechol-O-methyltransferase Inhibitors by Differential Competition Capture Compound Mass Spectrometry.
abstract: Structurally related inhibitors of a shared therapeutic target may differ regarding potential toxicity issues that are caused by different off-target bindings. We devised a differential competition capture compound mass spectrometry (dCCMS) strategy to effectively differentiate off-target profiles. Tolcapone and entacapone are potent inhibitors of catechol-O-methyl transferase (COMT) for the treatment of Parkinson's disease. Tolcapone is also known for its hepatotoxic side effects even though it is therapeutically more potent than entacapone. Here, we identified 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) as a possible toxicity-causing off-target of tolcapone, and this protein is not bound by the less toxic COMT inhibitor entacapone. Moreover, two novel compounds from a focused library synthesized in-house, N(2),N(2),N(3),N(3)-tetraethyl-6,7-dihydroxy-5-nitronaphthalene-2,3-dicarboxamide and 5-(3,4-dihydroxy-5-nitrobenzylidene)-3-ethylthiazolidine-2,4-dione, were utilized to gain insight into the structure-activity relationships in binding to COMT and the novel off-target HIBCH. These compounds, especially N(2),N(2),N(3),N(3)-tetraethyl-6,7-dihydroxy-5-nitronaphthalene-2,3-dicarboxamide, could serve as starting point for the development of improved and more specific COMT inhibitors.
authors.affiliation: Caprotec Bioanalytics GmbH , Magnusstraße 11, 12489 Berlin, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: von Kleist
authors.affiliation: Caprotec Bioanalytics GmbH , Magnusstraße 11, 12489 Berlin, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Michaelis
authors.affiliation: Caprotec Bioanalytics GmbH , Magnusstraße 11, 12489 Berlin, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Bartho
authors.affiliation: Caprotec Bioanalytics GmbH , Magnusstraße 11, 12489 Berlin, Germany.
authors.forename: Olivia
authors.initials: O
authors.lastname: Graebner
authors.affiliation: Caprotec Bioanalytics GmbH , Magnusstraße 11, 12489 Berlin, Germany.
authors.forename: Marén
authors.initials: M
authors.lastname: Schlief
authors.affiliation: Caprotec Bioanalytics GmbH , Magnusstraße 11, 12489 Berlin, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Dreger
authors.affiliation: Caprotec Bioanalytics GmbH , Magnusstraße 11, 12489 Berlin, Germany.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Schrey
authors.affiliation: Caprotec Bioanalytics GmbH , Magnusstraße 11, 12489 Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Sefkow
authors.affiliation: Caprotec Bioanalytics GmbH , Magnusstraße 11, 12489 Berlin, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Kroll
authors.affiliation: Caprotec Bioanalytics GmbH , Magnusstraße 11, 12489 Berlin, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Koester
authors.affiliation: Caprotec Bioanalytics GmbH , Magnusstraße 11, 12489 Berlin, Germany.
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
mesh_terms: D002394:Catechol O-Methyltransferase / Q000378:metabolism*; D065098:Catechol O-Methyltransferase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D006801:Humans; D013058:Mass Spectrometry; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D065098:Catechol O-Methyltransferase Inhibitors; D002394:Catechol O-Methyltransferase