Identification of Hck Inhibitors As Hits for the Development of Antileukemia and Anti‐HIV Agents |
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| Authors: | Dr. Cristina Tintori Ilaria Laurenzana Francesco La Rocca Dr. Federico Falchi Prof. Fabio Carraro Alba Ruiz Prof. José A. Esté Miroslava Kissova Dr. Emmanuele Crespan Prof. Giovanni Maga Prof. Mariangela Biava Dr. Chiara Brullo Prof. Silvia Schenone Prof. Maurizio Botta |
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| Affiliation: | 1. Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. De Gasperi 2, 53100 Siena (Italy);2. IRCCS‐Centro di Riferimento Oncologico Basilicata (CROB), Laboratory of Preclinical and Translational Research, Via Padre Pio 1, Rionero in Vulture 85028 Potenza (Italy);3. Department of Pharmacy and Biotechnology, Alma Mater Studiorum, Università di Bologna, Via Belmeloro 6, 40126 Bologna (Italy);4. Dipartimento di Medicina Molecolare e dello Sviluppo, Università degli Studi di Siena, Via A. De Gasperi 2, 53100 Siena (Italy);5. Irsicaixa, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona (Spain);6. Istituto di Genetica Molecolare, IGM‐CNR, Via Abbiategrasso 207, 27100 Pavia (Italy);7. Dipartimento di Chimica e Tecnologie del Farmaco, Università La Sapienza, Piazzale Aldo Moro 5, 00185 Roma (Italy);8. Dipartimento di Scienze Farmaceutiche, University of Genoa, Viale Benedetto XV 3, 16132 Genova (Italy);9. Biotechnology College of Science and Technology, Temple University, Biolife Science Building, Suite 333, 1900 North 12th Street, Philadelphia, PA 19122 (USA) |
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| Abstract: | Hematopoietic cell kinase (Hck) is a member of the Src family of non‐receptor protein tyrosine kinases. High levels of Hck are associated with drug resistance in chronic myeloid leukemia. Furthermore, Hck activity has been connected with HIV‐1. Herein, structure‐based drug design efforts were aimed at identifying novel Hck inhibitors. First, an in‐house library of pyrazolo[3,4‐d]pyrimidine derivatives, which were previously shown to be dual Abl and c‐Src inhibitors, was analyzed by docking studies within the ATP binding site of Hck to select the best candidates to be tested in a cell‐free assay. Next, the same computational protocol was applied to screen a database of commercially available compounds. As a result, most of the selected compounds were found active against Hck, with Ki values ranging from 0.14 to 18.4 μM , confirming the suitability of the computational approach adopted. Furthermore, selected compounds showed an interesting antiproliferative activity profile against the human leukemia cell line KU‐812, and one compound was found to block HIV‐1 replication at sub‐toxic concentrations. |
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| Keywords: | docking Hck HIV‐1 kinases leukemia |
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