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
posted on 2020-12-01, 21:34authored byQiqi Feng, Jiaying Zheng, Jie Zhang, Ming Zhao
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.