Structure-based design and biological evaluation of novel mTOR inhibitors as potential anti-cervical agents.

Peili Jiao; Yiyan Li; Xing Wu; Yuxi Wang; Beibei Mao; Hongwei Jin; Lihe Zhang; Liangren Zhang; Zhenming Liu

The mammalian target of rapamycin (mTOR) is a critical component of the PI3K-AKT signaling pathway. It is highly activated in cervical cancer, which continues to pose an important clinical challenge with an urgent need for new and improved therapeutic approaches. Herein, we describe the structure-based drug discovery and biological evaluation of a series of mTOR kinase inhibitors as potential anti-cervical cancer agents. The results of enzymatic activity assays supported C3 as a potential mTOR inhibitor, which exhibited high inhibitory activity with an IC50 of 1.57 μM. Molecular docking and dynamics simulation were conducted to predict the binding patterns, suggesting relationships between structure and activity. The anti-proliferative assay against diverse cancer cell lines was displayed subsequently, revealing that C3 exhibited significant proliferation inhibition against cervical cancer cell HeLa (IC50 = 0.38 μM) compared with other cell lines. Moreover, C3 could effectively reduce the expression of phospho-ribosomal S6 protein (p-S6) in HeLa cells in a dose-dependent manner. Noteworthily, mTOR signaling and other cellular pathways might contribute to the significant effect of C3 against cervical cancer simultaneously. These data indicated that C3 represented a good lead molecule for further development as a therapeutic agent for cervical cancer treatment.

MTOR inhibitors; STRUCTURE-activity relationships; HELA cells; CERVICAL cancer; MOLECULAR docking

Journal of Chinese Pharmaceutical Sciences, 2020, Vol 29, Issue 9, p603

1003-1057

Academic Journal

10.5246/jcps.2020.09.056