title: Incorporation of metabolically stable ketones into a small molecule probe to increase potency and water solubility.
abstract: Introducing a reactive carbonyl to a scaffold that does not otherwise have an electrophilic functionality to create a reversible covalent inhibitor is a potentially useful strategy for enhancing compound potency. However, aldehydes are metabolically unstable, which precludes the use of this strategy for compounds to be tested in animal models or in human clinical studies. To overcome this limitation, we designed ketone-based functionalities capable of forming reversible covalent adducts, while displaying high metabolic stability, and imparting improved water solubility to their pendant scaffold. We tested this strategy on the ferroptosis inducer and experimental therapeutic erastin, and observed substantial increases in compound potency. In particular, a new carbonyl erastin analog, termed IKE, displayed improved potency, solubility and metabolic stability, thus representing an ideal candidate for future in vivo cancer therapeutic applications.
authors.affiliation: Department of Biological Sciences, Columbia University, 550 West 120th Street, 1208 Northwest Corner Building, MC 4846, New York, NY 10027, United States.
authors.forename: Marie-Helene
authors.initials: MH
authors.lastname: Larraufie
authors.affiliation: Department of Biological Sciences, Columbia University, 550 West 120th Street, 1208 Northwest Corner Building, MC 4846, New York, NY 10027, United States.
authors.forename: Wan Seok
authors.initials: WS
authors.lastname: Yang
authors.affiliation: Department of Chemistry, Columbia University, New York, NY 10027, United States.
authors.forename: Elise
authors.initials: E
authors.lastname: Jiang
authors.affiliation: Brain Science Institute, Johns Hopkins Medicine, Baltimore, United States.
authors.forename: Ajit G
authors.initials: AG
authors.lastname: Thomas
authors.affiliation: Brain Science Institute, Johns Hopkins Medicine, Baltimore, United States; Department of Neurology, Johns Hopkins Medicine, Baltimore, United States.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
authors.affiliation: Department of Biological Sciences, Columbia University, 550 West 120th Street, 1208 Northwest Corner Building, MC 4846, New York, NY 10027, United States; Department of Chemistry, Columbia University, New York, NY 10027, United States; Howard Hughes Medical Institute, Columbia University, New York, NY 10027, United States. Electronic address: bstockwell@columbia.edu.
authors.forename: Brent R
authors.initials: BR
authors.lastname: Stockwell
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007659:Ketones / Q000737:chemistry* / Q000378:metabolism; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry*
chemical_list: D007659:Ketones; D010879:Piperazines; D054852:Small Molecule Libraries; C477224:erastin; D014867:Water
keywords: Covalent; Erastin; Ferroptosis; Metabolic stability; Reactive carbonyl