A Combination Strategy to Inhibit Pim-1: Synergism between Noncompetitive and ATP-Competitive Inhibitors

Authors

  • Dr. Mattia Mori,

    1. Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena (Italy)
    2. Dipartimento di Chimica e Tecnologie del Farmaco, Università di Roma “La Sapienza”, Piazzale A. Moro 5, 00185 Roma (Italy)
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    • Authors equally contributed to this work.

  • Dr. Cristina Tintori,

    1. Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena (Italy)
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    • Authors equally contributed to this work.

  • Dr. Robert Selwyne Arul Christopher,

    1. Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena (Italy)
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  • Dr. Marco Radi,

    1. Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena (Italy)
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  • Prof. Silvia Schenone,

    Corresponding author
    1. Dipartimento di Farmacia, Sezione di Chimica del Farmaco e del Prodotto Cosmetico, University of Genoa, Viale Benedetto XV 3, 16132 Genova (Italy)
    • Dipartimento di Farmacia, Sezione di Chimica del Farmaco e del Prodotto Cosmetico, University of Genoa, Viale Benedetto XV 3, 16132 Genova (Italy)
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  • Dr. Francesca Musumeci,

    1. Dipartimento di Farmacia, Sezione di Chimica del Farmaco e del Prodotto Cosmetico, University of Genoa, Viale Benedetto XV 3, 16132 Genova (Italy)
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  • Dr. Chiara Brullo,

    1. Dipartimento di Farmacia, Sezione di Chimica del Farmaco e del Prodotto Cosmetico, University of Genoa, Viale Benedetto XV 3, 16132 Genova (Italy)
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  • Dr. Patrizia Sanità,

    1. Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, Università dell'Aquila, Via Vetoio (Coppito 2), 67100 Coppito, L'Aquila (Italy)
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  • Dr. Simona Delle Monache,

    1. Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, Università dell'Aquila, Via Vetoio (Coppito 2), 67100 Coppito, L'Aquila (Italy)
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  • Dr. Adriano Angelucci,

    1. Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, Università dell'Aquila, Via Vetoio (Coppito 2), 67100 Coppito, L'Aquila (Italy)
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  • Miroslava Kissova,

    1. Istituto di Genetica Molecolare (IGM-CNR), Via Abbiategrasso 207, 27100 Pavia (Italy)
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  • Dr. Emmanuele Crespan,

    1. Istituto di Genetica Molecolare (IGM-CNR), Via Abbiategrasso 207, 27100 Pavia (Italy)
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  • Dr. Giovanni Maga,

    1. Istituto di Genetica Molecolare (IGM-CNR), Via Abbiategrasso 207, 27100 Pavia (Italy)
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  • Prof. Maurizio Botta

    Corresponding author
    1. Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena (Italy)
    2. Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Building, Suite 333, 1900 N 12th St., Philadelphia, PA 19122 (USA)
    • Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena (Italy)
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Abstract

Pim-1 is a serine/threonine kinase critically involved in the initiation and progression of various types of cancer, especially leukemia, lymphomas and solid tumors such as prostate, pancreas and colon, and is considered a potential drug target against these malignancies. In an effort to discover new potent Pim-1 inhibitors, a previously identified ATP-competitive indolyl-pyrrolone scaffold was expanded to derive structure–activity relationship data. A virtual screening campaign was also performed, which led to the discovery of additional ATP-competitive inhibitors as well as a series of 2-aminothiazole derivatives, which are noncompetitive with respect to both ATP and peptide substrate. This mechanism of action, which resembles allosteric inhibition, has not previously been characterized for Pim-1. Notably, further evaluation of the 2-aminothiazoles indicated a synergistic inhibitory effect in enzymatic assays when tested in combination with ATP-competitive inhibitors. A synergistic effect in the inhibition of cell proliferation by ATP-competitive and ATP-noncompetitive compounds was also observed in prostate cancer cell lines (PC3), where all Pim-1 inhibitors tested in showed synergism with the known anticancer agent, paclitaxel. These results further establish Pim-1 as a target in cancer therapy, and highlight the potential of these agents for use as adjuvant agents in the treatment of cancer diseases in which Pim-1 is associated with chemotherapeutic resistance.

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