Identification of Hck Inhibitors As Hits for the Development of Antileukemia and Anti-HIV Agents

Identification of Hck Inhibitors As Hits for the Development of Antileukemia and Anti-HIV Agents

Online publication: 28/06/2013

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. Read abstract online in ChemMedChem

Authors: Dr. Cristina Tintori1, Ilaria Laurenzana2, Francesco La Rocca2, Dr. Federico Falchi1,3, Prof. Fabio Carraro4, Alba Ruiz5, Prof. José A. Esté5, Miroslava Kissova6, Dr. Emmanuele Crespan6, Prof. Giovanni Maga6, Prof. Mariangela Biava7, Dr. Chiara Brullo8, Prof. Silvia Schenone8, Prof. Maurizio Botta1,9,* 1Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. De Gasperi 2, 53100 Siena (Italy) 2IRCCS-Centro di Riferimento Oncologico Basilicata (CROB), Laboratory of Preclinical and Translational Research, Via Padre Pio 1, Rionero in Vulture 85028 Potenza (Italy) 3Department of Pharmacy and Biotechnology, Alma Mater Studiorum, Università di Bologna, Via Belmeloro 6, 40126 Bologna (Italy) 4Dipartimento di Medicina Molecolare e dello Sviluppo, Università degli Studi di Siena, Via A. De Gasperi 2, 53100 Siena (Italy) 5Irsicaixa, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona (Spain) 6Istituto di Genetica Molecolare, IGM-CNR, Via Abbiategrasso 207, 27100 Pavia (Italy) 7Dipartimento di Chimica e Tecnologie del Farmaco, Università La Sapienza, Piazzale Aldo Moro 5, 00185 Roma (Italy) 8Dipartimento di Scienze Farmaceutiche, University of Genoa, Viale Benedetto XV 3, 16132 Genova (Italy) 9Biotechnology College of Science and Technology, Temple University, Biolife Science Building, Suite 333, 1900 North 12th Street, Philadelphia, PA 19122 (USA)
  • Doi Code: doi: 10.1002/cmdc.201300204

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