The human antigen R (HuR) is an RNA-binding protein known to modulate the expression of target mRNA coding for proteins involved in inflammation, tumorigenesis, and stress responses and is a valuable drug target. We previously found that dihydrotanshinone-I (DHTS, 1) prevents the association of HuR with its RNA substrate, thus imparing its function. Herein, inspired by DHTS structure, we designed and synthesized an array of ortho-quinones (tanshinone mimics) using a function-oriented synthetic approach. Among others, compound 6a and 6n turned out to be more effective than 1, showing a nanomolar Kiand disrupting HuR binding to RNA in cells. A combined approach of NMR titration and molecular dynamics (MD) simulations suggests that 6a stabilizes HuR in a peculiar closed conformation, which is incompatible with RNA binding. Alpha screen and RNA-electrophoretic mobility shift assays (REMSA) data on newly synthesized compounds allowed, for the first time, the generation of structure activity relationships (SARs), thus providing a solid background for the generation of highly effective HuR disruptors.
Interfering with HuR-RNA Interaction: Design, Synthesis and Biological Characterization of Tanshinone Mimics as Novel, Effective HuR Inhibitors / L. Manzoni, C. Zucal, D.D. Maio, V.G. D'Agostino, N. Thongon, I. Bonomo, P. Lal, M. Miceli, V. Baj, M. Brambilla, L. Cerofolini, S. Elezgarai, E. Biasini, C. Luchinat, E. Novellino, M. Fragai, L. Marinelli, A. Provenzani, P. Seneci. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 61:4(2018 Feb 22), pp. 1483-1498.
|Titolo:||Interfering with HuR-RNA Interaction: Design, Synthesis and Biological Characterization of Tanshinone Mimics as Novel, Effective HuR Inhibitors|
MANZONI, LEONARDO PIERPAOLO [Membro del Collaboration Group]
SENECI, PIERFAUSTO (Corresponding)
|Parole Chiave:||Binding protein hur; au-rich element; messenger-RNA; molecular-dynamics; force-field; posttranscritptional regulation; dihydrotanshinone-I; breast-cancer; expression; identification|
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
Settore CHIM/06 - Chimica Organica
Settore CHIM/01 - Chimica Analitica
|Data di pubblicazione:||22-feb-2018|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1021/acs.jmedchem.7b01176|
|Appare nelle tipologie:||01 - Articolo su periodico|