Targeting fatty acid synthase for cancer drug discovery: Retrospective analyses and outlook

Enhanced de novo lipogenesis is a hallmark of cancer cells, enabling their proliferation, metastasis, and resistance to therapy. Among key lipogenic enzymes, fatty acid synthase (FASN) is frequently overexpressed in cancer but minimally expressed in most normal adult tissues, making it an appealing drug target. Human FASN is the sole cytosolic type I enzyme responsible for the de novo synthesis of palmitate. It is a homodimer of 270 kDa multidomain protein, functioning like an automatic assembly line. Its acyl carrier protein domain serves as a flexible arm, transporting the elongating acyl chain through other enzymatic domains responsible for chain elongation and modification, including malonyl/acetyltransferase, β-ketoacyl synthase, enoyl reductase, β-ketoacyl reductase, dehydrase, and thioesterase. The process begins at the malonyl/acetyltransferase domain, where the acetyl and malonyl groups from acetyl-CoA and malonyl-CoA, respectively, are transferred to the acyl carrier protein. FASN has been validated to play vital roles in promoting cancer progression, supporting cancer cell survival, reprogramming lipid metabolism, modulating oncogenic signaling pathways, and inducing drug resistance. Over the past 2 decades, significant progress has been made in developing inhibitors targeting different domains of FASN, including structure-based drug design, repurposing existing drugs, and nature-derived compounds with FASN-inhibitory properties. Despite these efforts, only a handful of inhibitors have entered clinical trials, such as 3-V Biosciences-2640 (denifanstat) and repurposed omeprazole, and none have received regulatory approval to date. In this review, we critically evaluate FASN-targeting strategies, highlight domain-specific targeting challenges, and discuss emerging insights that may help overcome current limitations, aiming to guide future discovery and optimization of FASN-targeted therapeutics. SIGNIFICANCE STATEMENT: Enhanced lipogenesis and fatty acid synthase overexpression in cancer make this multidomain enzyme an attractive target for therapy and overcoming drug resistance. Despite progress with novel and repurposed inhibitors, none have gained approval. This review critically examines past efforts, current challenges, and offers insights to guide future development of effective fatty acid synthase-targeting cancer therapeutics.