Synthesis and In Vitro Evaluation of 2-[3-(2-Aminoethyl)-1H-indol-1-yl]-N-benzylquinazolin-4-amine as a Novel p97/VCP Inhibitor Lead Capable of Inducing Apoptosis in Cancer Cells.

P97/VCP, an endoplasmic reticulum associated protein, belongs to AAA ATPase family, ubiquitous ATPases associated with various cellular activities. Recent research has elucidated the roles of p97/VCP and evaluated its potential as a therapeutic target for some kinds of cancer diseases. We screened the small molecule compounds from a previously established library and found promise in the compound 2-[3-(2-aminoethyl)-1H-indol-1-yl]-N-benzylquinazolin-4-amine (FQ393). Data from docking simulation indicates FQ393 acts as an ATP competitor, and ATPase activity assays showed FQ393 was an inhibitor of p97/VCP. Furthermore, in vitro FQ393 is able to promote apoptosis and prohibit proliferation in a variety of cancer cell lines. Using comparative proteomic profiling of HCT-116 cells, we found significantly different canonical KEGG pathways, which revealed that the protein changes in FQ393 groups were associated with p97/VCP or tumor-related pathways. The present data suggests that FQ393 exerts antitumor activity, at least in part through p97/VCP inhibition.