Presents the Friday Keck Center Teleconference*
An anticancer C-Kit kinase inhibitor
is re-engineered to make it more active and less cardiotoxic
Ariel Fernandez, Ph.D.,
Karl F. Hasselmann Professor of Bioengineering
Rice University
4:00 pm Friday
Nov. 16th , 2007
(Refreshments at 3:45)
5.521 Levin Hall
Abstract: Kinase targeting is central to drug-based cancer therapy. However, modulating side effects remains challenging mainly because kinases are evolutionarily and hence structurally related. Thus, the cardiotoxicity of powerful anticancer drug imatinib has been attributed to its impact on a primary target, the Bcr-Abl kinase. Motivated by this finding, and guided by across-target differences in the de-wetting patterns of ligand-binding regions, we sculpted a discriminating modification of imatinib that hampers Bcr-Abl inhibition, re-focuses the impact on C-Kit kinase and promotes JNK inhibition, as needed to reinforce prevention of cardiotoxicity. We delineated the molecular blueprint for target discrimination through in-vitro assays and through a phage-display kinase screening library. By assaying for antitumor activity on different cell lines and through immunoblots, we demonstrated controlled inhibitory impact in vivo. Finally, we established the therapeutic impact of the engineered compound in a novel GIST animal model and corroborated a significant reduction in cardiotoxicity. (http://www.owlnet.rice.edu/~arifer/)
