Design, Synthesis and Biological Evaluation of Novel <i>1H</i>-benzo[d]imidazole Derivatives as Fatty Acid Synthase (FASN) Inhibitors for Cancer Treatment

Abstract

FASN is a metabolic oncoprotein that is overexpressed in multiple cancers and regulates the fatty acid requirements of proliferating cells. Thus, FASN has been proposed as a promising target for anticancer drug discovery. Herein, we report the de novo design and synthesis of small-molecule FASN inhibitors (CTL) that targets breast and colorectal cancer. Our structure–activity relationship studies led to the identification of CTL-1 and CTL-7 as potent, selective FASN inhibitors with IC50 values of 2.5 and 3.0 µM respectively. CTL-1 and CTL-7 inhibited the proliferation of colon cancer cells (HCT-116 and CaCO2) in and of breast cancer cells ( MCF-7 and MDA-MB-231) at less than 10 µM concentration. However, in the non-cancerous cell line HEK-293, the IC50 of CTL-1 and CTL-7 was above 30 µM. Further, cell cycle analysis and apoptosis induction studies of CTL-1 and CTL-7 in HCT-116 cells revealed S-phase arrest along with a prolonged apoptotic effect. Western blot analysis of CTL-1 and CTL-7 established FASN pathway participation in causing cancer cell apoptosis. Molecular dynamics simulation studies of the compounds in KR-domain of the target indicate that CTL-1 and CTL-7 have a high affinity of for the FASN enzyme.

Keywords

• fatty acid synthase inhibitor
• cancer
• apoptosis
• cell cycle
• enzyme inhibition
• MD simulation