title: Identification and mechanistic characterization of low-molecular-weight inhibitors for HuR.
abstract: Careful regulation of mRNA half-lives is a fundamental mechanism allowing cells to quickly respond to changing environmental conditions. The mRNA-binding Hu proteins are important for stabilization of short-lived mRNAs. Here we describe the identification and mechanistic characterization of the first low-molecular-weight inhibitors for Hu protein R (HuR) from microbial broths (Actinomyces sp.): dehydromutactin (1), MS-444 (2) and okicenone (3). These compounds interfere with HuR RNA binding, HuR trafficking, cytokine expression and T-cell activation. A mathematical and experimental analysis of the compounds' mode of action suggests that HuR homodimerizes before RNA binding and that the compounds interfere with the formation of HuR dimers. Our results demonstrate the chemical drugability of HuR; to our knowledge HuR is the first example of a drugable protein within the Hu family. MS-444, dehydromutactin and okicenone may become valuable tools for studying HuR function. An assessment of HuR inhibition as a central node in malignant processes might open up new conceptual routes toward combatting cancer.
authors.affiliation: Novartis Institutes for Biomedical Research, Discovery Technologies, Brunnerstr. 59, A-1235 Vienna, Austria. nicole-claudia.meisner@novartis.com
authors.forename: Nicole-Claudia
authors.initials: NC
authors.lastname: Meisner
authors.forename: Martin
authors.initials: M
authors.lastname: Hintersteiner
authors.forename: Kurt
authors.initials: K
authors.lastname: Mueller
authors.forename: Roman
authors.initials: R
authors.lastname: Bauer
authors.forename: Jan-Marcus
authors.initials: JM
authors.lastname: Seifert
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Naegeli
authors.forename: Johannes
authors.initials: J
authors.lastname: Ottl
authors.forename: Lukas
authors.initials: L
authors.lastname: Oberer
authors.forename: Christian
authors.initials: C
authors.lastname: Guenat
authors.forename: Serge
authors.initials: S
authors.lastname: Moss
authors.forename: Nathalie
authors.initials: N
authors.lastname: Harrer
authors.forename: Maximilian
authors.initials: M
authors.lastname: Woisetschlaeger
authors.forename: Christof
authors.initials: C
authors.lastname: Buehler
authors.forename: Volker
authors.initials: V
authors.lastname: Uhl
authors.forename: Manfred
authors.initials: M
authors.lastname: Auer
mesh_terms: D000190:Actinomyces / Q000378:metabolism; D000873:Anthracenes / Q000737:chemistry; D000890:Anti-Infective Agents / Q000737:chemistry; D000954:Antigens, Surface / Q000737:chemistry*; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D005454:Fluorescence Polarization; D005663:Furans / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008962:Models, Theoretical; D008969:Molecular Sequence Data; D009284:Naphthols / Q000737:chemistry; D011753:Pyrones / Q000737:chemistry; D016601:RNA-Binding Proteins / Q000737:chemistry*
chemical_list: D000873:Anthracenes; D000890:Anti-Infective Agents; D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D005663:Furans; D009284:Naphthols; D011753:Pyrones; D016601:RNA-Binding Proteins; C504637:mutactin; C071011:okicenone; C096620:5,8-dihydroxy-3-methyl-4-(9H)-naphtho(2,3-c)furanone