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Identification of novel inhibitors of BCR-ABL tyrosine kinase via virtual screening.

Abstract：

:Inhibition of BCR-ABL tyrosine kinase activity has shown to be essential for the treatment of chronic myelogenous leukemia (CML). However, drug resistance has quickly arisen in recent clinical trials for STI571 (Gleevec), which is the first approved drug of CML by inhibiting ABL tyrosine kinase. It is desirable to develop new types of ABL tyrosine kinase inhibitors that may overcome this drug resistance problem. Here we present the discovery of novel inhibitors targeted at the catalytic domain of ABL tyrosine kinase by using three-dimensional database searching techniques. From a database containing 200,000 commercially available compounds, the top 1000 compounds with the best DOCK energy score were selected and subjected to structural diversity and drug likeness analysis, 15 compounds were submitted for biological assay. Eight out of the 15 showed inhibitory activity against K562 cells with IC(50) value ranging from 10 to 200 microM. Two promising compounds showed inhibition in further ABL tyrosine phosphorylation assay. It is anticipated that those two compounds can serve as lead compounds for further drug design and optimization.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Peng H,Huang N,Qi J,Xie P,Xu C,Wang J,Yang C

doi

10.1016/j.bmcl.2003.08.014

subject

Has Abstract

pub_date

2003-11-03 00:00:00

pages

3693-9

issue

21

eissn

0960-894X

issn

1464-3405

pii

S0960894X03008424

journal_volume

13

pub_type

杂志文章

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