NSC 228155, a EGFR Activator, Inhibits KIX-KID Interaction
CREB (cAMP response element-binding protein) is a cellular transcription factor. It activates transcription by binding to CBP (CREB-binding protein) domains. CREB interacts with CPB involving kinase-inducible domain (KID) from CREB and KID-interacting domain (KIX) from CBP. Solid and liquid tumor tissues often over-express or over-activate CREB. Thus, CREB becomes a hot spot for cancer research. To find out more inhibitors of CREB or CBP, researchers screened a series of compounds. They discover that NSC 228155 is a potent inhibitor of KIX-KID interaction.
How does NSC 228155 function by targeting KIX-KID interaction? The reporters carry out a set of experiments to find out the mechanism of the inhibitor.
In the beginning, Fuchun Xie, et al., screened a variety of compounds with the split RLuc assay. The concentration of the compounds is of 10 μM.
Then, researchers synthesized and purified the compounds based on the screening results. They measured the bioactivity of the synthetic NSC 228155 (Compound 1). NSC 228155 blocks KIX-KID interaction in a dose-dependent manner. The IC50 value is 0.36 μM.
Subsequently, in the cellular assay, HEK 293T cells were transfected with CRE-RLuc, treated with different concentration of NSC 228155. As a result, NSC 228155 inhibited CREB-mediated gene transcription, with an IC50 value of of 2.09 μM. However, NSC 228155 was not highly selective in the inhibition of KIX-KID interaction in living HEK 293T cells. It also suppressed VP16-CREB-mediated gene transcription with an IC50 value of 6.14 μM.
In summary, NSC 228155 is a potent inhibitor of KIX-KID interaction. But it is not highly selective in CREB-mediated gene transcription. Further studies need to be done to find out more products to treat for cancer.
Xie F, et al. Bioorg Med Chem Lett. 2013 Oct 1;23(19):5371-5.