| Protein kinases constitute one of the largest and most functionally diverse protein families, involved in most cellular pathways. They are of crucial importance for signal transduction, and their deregulation is related to numerous human diseases, including cancer. Among kinases, c-Abl and c-Src are of particular interest for cancer research. The BCR-Abl fusion protein, is the initial cause of chronic myeloid leukemia disease (CML) (1). CML is treated with the powerful anti-cancer drug Imatinib, which acts as ATP-competitor. Imatinib, however, is not so selective and targets numerous kinases(2), beside c-Abl and c-Src, like c-KIT, PDGFR, Syk, Lck and many others, showing towards some of them a lack of activity. For instance it effectively inhibits BCR-Abl (IC50=0.2 uM) but not Src (3), no matter their high sequence homology (47%), neither that the bound structure of Src with Imatinib is very similar to that of Abl with Imatinib. In the same way, the drug inhibits c-KIT (IC50=0.41 uM) but not Syk (3), although they share the same sequence identity of 40% with both Abl and Src. Striking is the case of Lck, quite effectively inhibited by Imatinib (IC50=9 uM) (3), despite the high identity with Src kinase (70%). Detecting the features responsible for the observed differences is essential for the development of new effective anticancer drugs but also useful to identify possible hallmarks of the variegate kinase superfamily. Recently, in our work concerning the two kinases c-Abl and c-Src, we have shown that the difference in the Imatinib activity can be attributed to a larger flexibility of c-Abl(4). Now in this follow up work we have extended the analysis to the other cited kinases, analyzing their flexibility profiles. Performing classical molecular dynamic simulations, followed by RMSF analysis, we have identified regions with a higher flexibility common to all the kinases sensitive to Imatinib (c-Abl, c-KIT and also Lck) and a more rigid profile in the same regions for those not responding to the drug (c-Src and Syk). From these preliminary results we could recognize flexibility as a possible hallmark of all the studied kinases sensitive to Imatinib, probably due to its paramount importance for active site accessibility. (1) Rowley, J.D. Nature 1973, 243, 290–293. (2) Lee SJ, Wang JYJ. Journal of Biology. 2009. (3) Deininger, M.; Buchdunger, E.; Druker, B. J. Blood 2005, 105, 2640–2653. (4) Lovera S, Sutto L, Boubeva R, et al. Journal of the American Chemical Society. 2011:8-11. |
|