Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue -, Pages 2-25Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2012.06.005
Keywords
Tyrosine kinase inhibitors; TAM subfamily; Molecular modelling; Docking
Categories
Funding
- Centre National de la Recherche Scientifique
- Institut Curie
- INCa
- Ligue Nationale Contre le Cancer
- French Ministry of Research
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The TAM subfamily of Receptor Tyrosine Kinases (RTKs) contains three human proteins of therapeutical interest, Axl, Mer, and Tyro3. Our goal was to design a type II inhibitor specific for this family, i.e. able to interact with the allosteric pocket and with the hinge region of the kinase. We report the synthesis of several series of purine analogues of BMS-777607. The structural diversity of the designed inhibitors was expected to modify the interactions formed in the binding site and consequently to modulate their selectivity profiles. The most potent inhibitor 6g exhibits K(d)s of 39, 42, 65 and 200 nM against Axl, Mer, Met and Tyro3 respectively. Analysis of the affinity of 6g for active and inactive forms of Abl1, an RTK protein that does not belong to the TAM subfamily, together with the binding modes of 6g predicted by docking studies, indicates that 6g displays some selectivity for the TAM family and may act as a type II inhibitor. Crown Copyright (C) 2012 Published by Elsevier Masson SAS. All rights reserved.
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