Article: A Combination Strategy to Inhibit Pim-1: Synergism between Noncompetitive and ATP-Competitive Inhibitors.Mattia Mori, Cristina Tintori, Robert Selwyne Arul Christopher, Marco Radi, Silvia Schenone, Francesca Musumeci, Chiara Brullo, Patrizia Sanità, Simona Delle Monache, Adriano Angelucci, Miroslava Kissova, Emmanuele Crespan, Giovanni Maga, Maurizio Botta[show abstract] [hide abstract]
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.ChemMedChem 03/2013; 8(3):484-96. · 3.15 Impact Factor
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ABSTRACT: The recent launch onto the market of five VEGFR inhibitors indicates the therapeutic value of these agents and the importance of the research in the field of angiogenesis inhibitors for future oncologic therapy. In this perspective we briefly report the inhibitors which are in clinical use, while we dedicate two wider sections to the compounds which are in clinical trials and to the new derivatives appearing in the literature. We especially consider the medicinal chemistry aspect of the topic, report the structure-activity relationship studies and the binding mode of some inhibitors as well as the biological data of the compounds discovered in the past five years.Journal of Medicinal Chemistry 10/2012; · 4.80 Impact Factor
Article: A combined targeted/phenotypic approach for the identification of new antiangiogenics agents active on a zebrafish model: from in silico screening to cyclodextrin formulation.Marco Radi, Lasse Evensen, Elena Dreassi, Claudio Zamperini, Marialessandra Caporicci, Federico Falchi, Francesca Musumeci, Silvia Schenone, James B Lorens, Maurizio Botta[show abstract] [hide abstract]
ABSTRACT: A combined targeted/phenotypic approach for the rapid identification of novel antiangiogenics with in vivo efficacy is herein reported. Considering the important role played by the tyrosine kinase c-Src in the regulation of tumour angiogenesis, we submitted our in-house library of c-Src inhibitors to a sequential screening approach: in silico screening on VEGFR2, in vitro screening on HUVEC cells, ADME profiling, formulation and in vivo testing on a zebrafish model. A promising antiangiogenic candidate able to interfere with the vascular growth of a zebrafish model at low micromolar concentration was thus identified.Bioorganic & medicinal chemistry letters 07/2012; 22(17):5579-83. · 2.65 Impact Factor
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ABSTRACT: The cytoplasmatic tyrosine in kinase c-Src is involved in the regulation of several cell functions including adhesion, invasion, proliferation, survival and angiogenesis. Src activity is strictly regulated in healthy cells, whereas its overexpression or hyperactivation plays a critical role during tumor development. Recently it has been suggested that the oncogenic potential of Src is linked to its role in the activation of key signalling molecules involved in several cell pathways, rather than its direct activity. For all these reasons Src represents a promising therapeutic target for the treatment of tumors. In this article a number of examples of c-Src inhibitors appeared in selected patents from 2006 to early 2011 will be reported, focusing on their chemical features and, whenever possible, on structure- activity relationships and mechanism of action. Examples of type I or II ATP-competitive inhibitors or substrate competitive inhibitors will be presented. The research in this field is very active and will probably lead to the discovery of therapeutically useful compounds, both c-Src selective and multitargeted inhibitors, that acting on different cell pathways could be more effective in blocking cancer development. However, only the results of clinical trials will show in the near future the most promising compounds.Current Medicinal Chemistry 10/2011; 18(33):5061-78. · 4.86 Impact Factor
Article: Targeting the human DEAD-box polypeptide 3 (DDX3) RNA helicase as a novel strategy to inhibit viral replication.[show abstract] [hide abstract]
ABSTRACT: Compounds currently used for the treatment of HIV-1 Infections are targeted to viral proteins. However, the high intrinsic mutation and replication rates of HIV-1 often lead to the emergence of drug resistant strains and consequent therapeutic failure. On this basis, cellular cofactors represent attractive new targets for HIV-1 chemotherapy, since targeting a cellular factor that is required for viral replication should help to overcome the problem of viral resistance. We and others have recently reported the identification of compounds suppressing HIV-1 replication by targeting the cellular DEAD-box helicase DDX3. These results provide a proof-of-principle for the feasibility of blocking HIV-1 infection by rendering the host cell environment less favorable for the virus. The rationale for such an approach and its implications in potentially overcoming the problem of drug resistance related to drugs targeting viral proteins will be discussed in the context of the known cellular functions of the DEAD-box helicase DDX3.Current Medicinal Chemistry 06/2011; 18(20):3015-27. · 4.86 Impact Factor
Dr. Marco Radi was born in Massa Marittima (GR), Italy in 1974. He received a Master (5 years Laurea) in Medicinal Chemistry at the University of Siena (Italy) in 2000 (Marks: 110/110 cum laude) and a PhD in Medicinal Chemistry from the same University in 2004. He spent one year as Postdoctoral Research Associate at the University of Georgia (USA) working with Prof. David C.K. Chu on the synthesis of Troxacitabine prodrugs and Neplanocin A analogues as potential anticancer and antiviral agents. From January 2006 till January 2010 he worked as Postdoctoral Research Associate at the University of Siena in collaboration with Prof. Maurizio Botta. In the period February-June 2010, he received a fellowship from the same University for a research on new antiviral agents. From July 2010 till December 2011, he worked as Postdoctoral Research Associate (Ricercatore a Tempo Determinato) at the University of Siena.
Since december 2011, Dr. Radi is Assistant Professor at the Faculty of Pharmacy of the University of Parma.
His Research interests are in the field of Organic, Analytical and Medicinal Chemistry with particular interest in the Drug Design and Synthesis of novel Antiviral, Anticancer and Antitubercular agents.