Feng Qiqi, Zheng Jiaying, Zhang Jie, Zhao Ming
School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, People's Republic of China.
Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Capital Medical University, Beijing 100069, People's Republic of China.
ACS Omega. 2020 Dec 1;5(49):31784-31791. doi: 10.1021/acsomega.0c04478. eCollection 2020 Dec 15.
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)-1-indol-1-yl]--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.
P97/VCP是一种内质网相关蛋白，属于AAA ATP酶家族，即与各种细胞活动相关的普遍存在的ATP酶。最近的研究阐明了p97/VCP的作用，并评估了其作为某些癌症疾病治疗靶点的潜力。我们从先前建立的文库中筛选小分子化合物，发现化合物2-[3-(2-氨基乙基)-1-吲哚-1-基]苄基喹唑啉-4-胺（FQ393）具有潜力。对接模拟数据表明FQ393作为ATP竞争者，ATP酶活性测定表明FQ393是p97/VCP的抑制剂。此外，体外实验中FQ393能够促进多种癌细胞系的凋亡并抑制增殖。通过对HCT-116细胞进行比较蛋白质组分析，我们发现显著不同的经典KEGG途径，这表明FQ393组中的蛋白质变化与p97/VCP或肿瘤相关途径有关。目前的数据表明，FQ393至少部分通过抑制p97/VCP发挥抗肿瘤活性。
