title: Eeyarestatin I derivatives with improved aqueous solubility.
abstract: Inhibition of p97 (also known as valosin-containing protein (VCP)), has been validated as a promising strategy for cancer therapy. Eeyarestatin I (EerI) blocks p97 through a novel mechanism of action and has favorable anti-cancer activities against cultured cancer cells. However, its poor aqueous solubility severely limits its in vivo applications. To circumvent this problem, we have identified EerI derivatives that possess improved aqueous solubility by introducing a single solubilizing group. These modified compounds preserved endoplasmic reticulum (ER) stress-inducing and antiproliferative activities as well as generally good in vitro metabolic properties, suggesting that these EerI derivatives could serve as candidates for further optimization.
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, United States.
authors.forename: Rui
authors.initials: R
authors.lastname: Ding
authors.affiliation: Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, United States.
authors.forename: Jiashu
authors.initials: J
authors.lastname: Xie
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Williams
authors.affiliation: Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, United States. Electronic address: chenx462@umn.edu.
authors.forename: Liqiang
authors.initials: L
authors.lastname: Chen
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects; D006801:Humans; D006835:Hydrazones / Q000737:chemistry* / Q000494:pharmacology; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D012995:Solubility; D014867:Water / Q000737:chemistry
chemical_list: C492847:1-(4-chlorophenyl)-3-(3-(4-chlorophenyl)-5,5-dimethyl-1-(3-(5-nitrofuran-2-yl)allyldienehydrazinocarbonylmethyl)-2-oxoimidazolidin-4-yl)-1-hydroxyurea; D051700:Activating Transcription Factor 3; D006835:Hydrazones; D014867:Water; D051701:Activating Transcription Factor 4; D006918:Hydroxyurea
keywords: EerI; Eeyarestatin I; Solubility; VCP; Valosin-containing protein; p97