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Identification of Hck Inhibitors As Hits for the Development of Antileukemia and Anti‐HIV Agents
Author(s) -
Tintori Cristina,
Laurenzana Ilaria,
La Rocca Francesco,
Falchi Federico,
Carraro Fabio,
Ruiz Alba,
Esté José A.,
Kissova Miroslava,
Crespan Emmanuele,
Maga Giovanni,
Biava Mariangela,
Brullo Chiara,
Sche Silvia,
Botta Maurizio
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300204
Subject(s) - identification (biology) , human immunodeficiency virus (hiv) , computational biology , drug discovery , virology , chemistry , medicine , biology , biochemistry , botany
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 K i values ranging from 0.14 to 18.4 μ M , 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.