Design, synthesis and biological evaluation of 2-phenylquinoxaline carbonyl piperazine derivatives as novel FASN inhibitors with anticancer activity.

Overexpression of fatty acid synthase (FASN) has been linked to the advancement of various cancers. FASN caters to the increased demand for lipids within tumor cells, facilitating tumor growth and progression, making it an attractive target for anticancer drug discovery. Herein we report a novel series of 2-phenylquinoxaline-6-carboxylic acid derivatives as novel potent FASN inhibitors with anticancer potential. Structure-activity relationship analysis demonstrated that all the synthesized compounds showed potent and selective cytotoxicity against the three cancer cell lines evaluated with IC values less than 10 μM. QNX-10 was identified as a promising lead molecule as it elicited potent FASN inhibition and selective cytotoxicity against the colorectal (HCT-116, Caco-2 cell lines) and breast cancer (MCF-7 cell line). Notably, QNX-10 induces apoptosis and cell cycle arrest at S-phase in HCT-116 cells in a dose-dependent manner. Western blot analysis indicated that QNX-10 inhibits FASN and promotes apoptosis in HCT-116 cells by upregulating pro-apoptotic protein Bax and downregulating anti-apoptotic protein Bcl-xL. Molecular docking and MD simulation studies with QNX-10 revealed the binding mode of the compound to the KR domain of FASN. Taken together, the study establishes compound QNX-10 to be a promising lead candidate for the development of anticancer therapeutics targeting the FASN enzyme.