Multifaceted In Silico Screening Strategies Identifies Potent Inhibitors Facilitating Inhibition of ZNF726 Activity in Breast Cancer

Studies documented by our lab established ZNF726 to potently augment the tumorigenic behavior of breast cancer cells by increasing cellular cholesterol levels. Therefore, Zinc finger protein 726 (ZNF726) can be considered an attractive therapeutic target for the treatment of breast cancer. Based on these views, this study aimed to identify potent inhibitors targeting ZNF726 activity utilizing a structure-based molecular docking method. Virtual screening with the LOPAC library led to the identification of zoledronic acid monohydrate as a top-hit compound featuring good docking and MMGBSA scores. Further, zoledronic acid monohydrate was found to inhibit the proliferation potential of breast cancer cells. Ectopic expression of ZNF726 led to an increase in the cholesterol levels of breast cancer cells. Further, this study confirms that zoledronic acid tends to decrease the cholesterol content in ZNF726-overexpressed cells along with an inhibitory effect on breast cancer cell proliferation. Conclusively, these findings suggested that the cholesterol pathway and oncogenic ZNF726 form an interdependent relationship, and therefore, targeting the cholesterol pathway may prove to be a promising strategy to inhibit oncogenic ZNF726 expression in breast cancer. Additionally, this study also reveals nine phytochemicals that might target ZNF726 activity, identified through virtual screening by the IMPPAT library. Three phytochemicals (Swertiamacroside, Terflavin A, and N-(3-Carboxy-2,3-dihydroxypropyl)-4-((carboxymethyl)amino) threonine) out of the nine phytochemicals are still unknown for their anticancer role which needs further exploration. Briefly, this study draws attention toward finding potential therapeutics against the carcinogenic effects of ZNF726 by multiple in silico approaches.