Identification of Direct Target Engagement Biomarkers for Kinase-Targeted Therapeutics
Figure 2
Bona fide substrates are not representative of PDK1 target inhibition.
A) The T-loop phosphorylation site on PDK1Ser241 is not modulated by PDK1 inhibitor treatment in PC3 cells whereas downstream substrates, such as p-AKTThr308 and p-RSKSer221, are affected. B) In PC3 cells the inhibition of p-RSKSer221 correlates with the enzymatic potency of PDK1 inhibitors (N = 147). C) LNCap cells don't exhibit a correlation between inhibition of p-AKTThr308, a bona fide PDK1 substrate (N = 279), and the D) enzymatic potency of PDK1 inhibitors (N = 82). E) Western blot of p-AKTThr308 and p-RSKSer221 in a variety of cell lines. F) PDK1 substrates are subject to feedback regulation and pathway cross-talk.