BMS-354825 binding mode in Ableson kinase
revealed by molecular docking studies
.

 

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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
2
Department of Oncology, McGill University, Montreal, Canada
3
Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH), Zurich, Switzerland
4
Laboratoire 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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