Kinase targeting is critical to drug-based cancer therapy, often geared at blocking the signal transduction governing cell fate and proliferation 1-7. Reducing cross reactivity by inhibitor design constitutes a challenge because kinases are evolutionarily, and hence structurally, related 1,7,8. Thus, Gleevec, an inhibitor of the CML (chronic myeloid leukemia 9) target Bcr-Abl 7,10,11 was later shown to impact the C-Kit kinase 12-14, a target for gastrointestinal stromal (GIST) tumors 13,15. Here we show how to reengineer the inhibitor guided by a structural discriminator that identifies differences in interfacial dehydration patterns 16 as Gleevec associates with different primary targets. Thus, we identify binding regions of C-Kit kinase susceptible to water attack and not conserved in Bcr-Abl, and modify the parental compound to selectively protect the vulnerabilities in C-Kit. By assaying the prototype molecule for antitumor activity on GIST13,15 and CML10 cell lines, we demonstrate drug specificity, subsequently corroborated by immunoblots. Finally, we identify a molecular signature for specificity in antitumor activity by contrasting cellular against test-tube assays.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA