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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. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer in females with extremely high lethality mainly due to the occurrence of metastasis, which is closely related to cancer stem-like cells (CSCs). It has been reported that CSC frequency in drug-resistant breast cancer and non-small cell lung cancer is reduced by activating dopamine D1 receptor (D1DR). In the present study, we aimed to investigate the effect of a compound C17 that can be used orally for breast cancer metastasis as well as the underlying mechanism involving the activation of D1DR. The confocal immunofluorescence analysis demonstrated that D1DR was up-regulated by C17. The cell survival and colony formation were inhibited by C17 through the detection by Sulforhodamine B colorimetric (SRB) assay and colony formation assay, respectively. Results from both wound healing assay and transwell assay demonstrated that C17 inhibited the migration of 4T1 cells. Flow cytometry analysis indicated that C17 significantly reduced the CSC frequency. In addition, C17 could inhibit the lung metastasis in 4T1 orthotopic mouse model of breast cancer without obvious toxicity, and it could up-regulate the expression of intratumoral E-cadherin and down-regulate the expressions of Snail and N-cadherin in primary breast tumor, which might be related to the activation of D1DR. Our findings provided a potential candidate compound for the treatment of metastatic breast cancer with good compliance and safety. [ABSTRACT FROM AUTHOR]