Recent advances in targeting the fatty acid biosynthetic pathway using fatty acid synthase inhibitors

ABSTRACT

Introduction: Elevated lipogenesis has been associated with a variety of diseases including obesity, cancer and nonalcoholic fatty liver disease (NAFLD). Fatty acid synthase (FASN) plays a pivotal role in de novo lipogenesis, making this multi-catalytic protein an attractive target for therapeutic intervention. Recently, the first FASN inhibitor successfully advanced through the drug development process and entered clinical evaluation in oncology.

Areas covered: This review discusses the biological roles of FASN in three prominent disease areas: cancer, obesity-related disorders and NAFLD. Recent advances in drug discovery strategies and design of newer FASN inhibitors are also highlighted.

Expert opinion: Despite the abundance of evidence linking the lipogenic pathway to cancer, progression of FASN-targeted molecules has been rather slow and challenging and no compounds have moved past the preclinical phase. The landscape has recently changed with the recent advancement of the first FASN inhibitor into clinical evaluation for solid tumors. Needless to say, the successful translation into the clinical setting will open opportunities for expanding the therapeutic utility of FASN inhibitors not just in oncology but in other diseases associated with elevated lipogenesis such as obesity, type 2 diabetes, and NAFLD.

KEYWORDS:

• Fatty acid synthase
• cancer
• lipogenesis
• malonyl-CoA
• metabolic enzymes
• non-alcoholic fatty liver disease
• obesity

Article highlights

• Fatty acid synthase (FASN) catalyzes the conversion of malonyl CoA and acetyl CoA to the saturated C16 fatty acid palmitate.

• The FASN mechanism has been elucidated with the aid of x-ray crystallography.

• FASN activity is a phenotype in many cancers and implicated in cancer progression, resistance and poor prognosis.

• FASN is a potential drug target for cancer, obesity and associated metabolic diseases.

• Polyphenol natural product based inhibitors show promise in oncology and diabetes.

• The first small molecule FASN inhibitor (TVB-2640) completed phase 1 for solid tumors.

• Small molecule keto reductase domain inhibitors from GlaxoSmithKline show promise as anticancer agents.

• Fasnall, a small molecule targeting the cofactor domain induced apoptosis in triple-negative breast cancer cells.

This box summarizes key points contained in the article.

Declaration of interest

Thelma S. Angeles and Robert L. Hudkins are both employees of Teva Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This manuscript has not been funded.