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 / Manzoni, Leonardo; Zucal, Chiara; Maio, Danilo Di; D'Agostino, Vito G; Thongon, Natthakan; Bonomo, Isabelle; Lal, Preet; Miceli, Marco; Baj, Vanessa; Brambilla, Marta; Cerofolini, Linda; Elezgarai, Saioa; Biasini, Emiliano; Luchinat, Claudio; Novellino, Ettore; Fragai, Marco; Marinelli, Luciana; Provenzani, Alessandro; Seneci, Pierfausto. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 2018/61:4(2018), pp. 1483-1498. [10.1021/acs.jmedchem.7b01176]

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

Zucal, Chiara;D'Agostino, Vito G;Thongon, Natthakan;Bonomo, Isabelle;Lal, Preet;Biasini, Emiliano;Provenzani, Alessandro;Seneci, Pierfausto
2018-01-01

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 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.
4
Manzoni, Leonardo; Zucal, Chiara; Maio, Danilo Di; D'Agostino, Vito G; Thongon, Natthakan; Bonomo, Isabelle; Lal, Preet; Miceli, Marco; Baj, Vanessa; Brambilla, Marta; Cerofolini, Linda; Elezgarai, Saioa; Biasini, Emiliano; Luchinat, Claudio; Novellino, Ettore; Fragai, Marco; Marinelli, Luciana; Provenzani, Alessandro; Seneci, Pierfausto
Interfering with HuR-RNA Interaction: Design, Synthesis and Biological Characterization of Tanshinone Mimics as Novel, Effective HuR Inhibitors / Manzoni, Leonardo; Zucal, Chiara; Maio, Danilo Di; D'Agostino, Vito G; Thongon, Natthakan; Bonomo, Isabelle; Lal, Preet; Miceli, Marco; Baj, Vanessa; Brambilla, Marta; Cerofolini, Linda; Elezgarai, Saioa; Biasini, Emiliano; Luchinat, Claudio; Novellino, Ettore; Fragai, Marco; Marinelli, Luciana; Provenzani, Alessandro; Seneci, Pierfausto. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 2018/61:4(2018), pp. 1483-1498. [10.1021/acs.jmedchem.7b01176]
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