Interfering with HuR-RNA Interaction: Design, Synthesis and Biological Characterization of Tanshinone Mimics as Novel, Effective HuR Inhibitors

  • J Med Chem. 2018 Feb 22;61(4):1483-1498. doi: 10.1021/acs.jmedchem.7b01176.
Leonardo Manzoni  1 ,  Chiara Zucal  2 ,  Danilo Di Maio  3 ,  Vito G D'Agostino  2 ,  Natthakan Thongon  2 ,  Isabelle Bonomo  2 ,  Preet Lal  2 ,  Marco Miceli  4 ,  Vanessa Baj  4 ,  Marta Brambilla  4 ,  Linda Cerofolini  5  6 ,  Saioa Elezgarai  7 ,  Emiliano Biasini  2  7 ,  Claudio Luchinat  6 ,  Ettore Novellino  8 ,  Marco Fragai  5  6 ,  Luciana Marinelli  8 ,  Alessandro Provenzani  2 ,  Pierfausto Seneci  4
Affiliations
  • 1. Institute of Molecular Science and Technology (ISTM) , CNR, Via Golgi 19, 20133 Milan, Italy.
  • 2. Centre for Integrative Biology (CIBIO), University of Trento , Via Sommarive 9, 38123 Povo, Trento, Italy.
  • 3. Scuola Normale Superiore , Piazza dei Cavalieri 7, I-56126 Pisa, Italy.
  • 4. Chemistry Department, University of Milan , Via Golgi 19, 20133 Milan, Italy.
  • 5. Consorzio Interuniversitario di Risonanze Magnetiche di Metallo Proteine (CIRMMP) , Via L. Sacconi 6, 50019 Sesto Fiorentino, Florence, Italy.
  • 6. CERM and Chemistry Department, University of Florence , Via della Lastruccia 3-13, 50019 Sesto Fiorentino, Florence, Italy.
  • 7. Istituto di Ricerche Farmacologiche Mario Negri , Milan, 20156, Italy.
  • 8. Pharmacy Department, University of Naples , Via Montesano 49, 80131 Naples, Italy.
PMID: 29313684 DOI: 10.1021/acs.jmedchem.7b01176
Abstract

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 Ki and 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.