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

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

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.

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