Sie befinden Sich nicht im Netzwerk der Universität Paderborn. Der Zugriff auf elektronische Ressourcen ist gegebenenfalls nur via VPN oder Shibboleth (DFN-AAI) möglich. mehr Informationen...
Identification of Hck Inhibitors As Hits for the Development of Antileukemia and Anti-HIV Agents
Ist Teil von
ChemMedChem, 2013-08, Vol.8 (8), p.1353-1360
Ort / Verlag
Weinheim: WILEY-VCH Verlag
Erscheinungsjahr
2013
Link zum Volltext
Quelle
Wiley Online Library - AutoHoldings Journals
Beschreibungen/Notizen
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.
Rational design: Virtual screening by cross‐docking identified various small molecules as hematopoietic cell kinase (Hck) inhibitors. Evaluation of the virtual hits in a cell‐free assay revealed that some compounds inhibit Hck at sub‐ micromolar concentrations. Simulations allowed the identification of key interactions in the inhibitor–kinase complexes.