Synthesis and Evaluation of Potential Inhibitors Targeting Fatty Acid Synthase in Cancer

Cancer cells undergo profound metabolic reprogramming to sustain uncontrolled growth and survival. Among these alterations, de novo fatty acid synthesis is upregulated to support membrane biogenesis, energy storage, and signaling. Fatty acid synthase (FASN), is the central enzyme responsible for long-chain fatty acid synthesis. This enzyme is markedly overexpressed in several cancer types and correlates with poor prognosis and therapeutic resistance. Thus, FASN represents a promising metabolic target for cancer therapy. In this study we sought to identify and evaluate small-molecule inhibitors targeting the β-ketoacyl reductase (KR) domain of FASN. Approximately 300,000 compounds were computationally screened using molecular docking in the crystal structure of the domain. Similarly, FDA-approved drugs were also computationally screened against FASN to explore drug repurposing as a potential strategy for accelerating therapeutic development. Top candidates from the screen that displayed strong binding affinities and favorable interactions were prioritized for synthesis and further evaluation. Three hit molecules were synthesized via multi-step organic reactions and were confirmed by NMR and mass spectrometry. The biological activity of these compounds was evaluated using MTT cell viability assays in cancer cell lines with elevated FASN expression, including HeLa (cervical) and PC-3 (prostate) cells. Preliminary data shows a reduction in cell viability with increasing concentration of the hit molecules. Ongoing work includes further biochemical evaluation to understand the FASN inhibitory effects and IC50 determination. Obtained results will help support FASN as a promising target for anticancer drug discovery and demonstrate the utility of integrating molecular docking, chemical synthesis, and experimental validation.