Leukemia, 2005, 19, 1267−1269.
C Gambacorti-Passerini1,2,
M Gasser3,4,
S Ahmed4,
S Assouline2 and L Scapozza4
1University
of Milano Bicocca and National Cancer Institute, Milan, Italy
2Department of Oncology, McGill University, Montreal, Canada
3Department of Chemistry and Applied Biosciences, Institute of
Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH),
Zurich, Switzerland
4Laboratoire de Chimie Thérapeutique, School of Pharmaceutical
Sciences, Geneva University, Genève, Switzerland
Correspondence: Prof. L Scapozza, Laboratoire de Chimie Thérapeutique,
School of Pharmaceutical Sciences, University of Geneva, Quai Ernest-Ansermet
30, 1211 Genève 4, Switzerland. Fax: +41 22 379 3360;
E-mail: Dr. Leonardo Scapozza
TO THE EDITOR
A new SRC-Abl dual inhibitor, BMS354825, has
recently been presented as a possible tool to overcome resistance to
imatinib in neoplasias caused by oncogenic variants of the tyrosine kinase
domain of Bcr-Abl. BMS354825 is able to inhibit in vitro and in vivo 14 of
15 imatinib-resistant Bcr-Abl mutants, while the T315I was clearly resistant
to the compound. It has been suggested that BMS354825 could fit into a
conformation of Abl different from the inactive one (ie the one that
imatinib preferentially binds).
To better understand imatinib and BMS354825 binding, the two molecules were
docked using the FLEXX software in different available structures of Abl:
1IEP Abl (closed conformation) in which the activation loop is closed, and
1M52 Abl (intermediate conformation) where the activation loop is open.
In both structures, the highly conserved DFG motif has a similar
conformation, with the phenylalanine residue pointing towards the ATP
binding site, while the aspartic acid residue points away from it,
indicating that the enzyme is still in its inactive form, that is, the one
unable to perform the catalytic reaction. Furthermore, a model of Abl with
the DFG in the productive conformation, with the aspartic acid residue
pointing towards the ATP binding pocket and the activation loop in the open
conformation (similar to those seen in the 1IR3 conformation and in the
human lympocyte kinase structure 3LCK), was generated (open conformation) to
study the effect of its orientation on the binding mode of these compounds.
The used docking protocol allowed us to reproduce accurately the available
binding orientations of imatinib and PD173955, as previously determined on
crystal structures.
Full article available at http://www.nature.com >>
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