Identification and mechanistic characterization of low-molecular-weight inhibitors for HuR.
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.
Meisner
Nicole-Claudia
NC
Novartis Institutes for Biomedical Research, Discovery Technologies, Brunnerstr. 59, A-1235 Vienna, Austria. nicole-claudia.meisner@novartis.com
Hintersteiner
Martin
M
Mueller
Kurt
K
Bauer
Roman
R
Seifert
Jan-Marcus
JM
Naegeli
Hans-Ulrich
HU
Ottl
Johannes
J
Oberer
Lukas
L
Guenat
Christian
C
Moss
Serge
S
Harrer
Nathalie
N
Woisetschlaeger
Maximilian
M
Buehler
Christof
C
Uhl
Volker
V
Auer
Manfred
M
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*
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