Broad Anti-tumor Activity of a Small Molecule that Selectively Targets the Warburg Effect and Lipogenesis

Malignant cells exhibit aerobic glycolysis (the Warburg effect) and become dependent on de novo lipogenesis, which sustains rapid proliferation and resistance to cellular stress. The nuclear receptor liver-X-receptor (LXR) directly regulates expression of key glycolytic and lipogenic genes. To disrupt these oncogenic metabolism pathways, we designed an LXR inverse agonist SR9243 that induces LXR-corepressor interaction. In cancer cells, SR9243 significantly inhibited the Warburg effect and lipogenesis by reducing glycolytic and lipogenic gene expression. SR9243 induced apoptosis in tumors without inducing weight loss, hepatotoxicity, or inflammation. Our results suggest that LXR inverse agonists may be an effective cancer treatment approach. [Display omitted] •Glycolysis and lipogenesis are key metabolic pathways in cancer•LXRs directly regulate glycolysis and lipogenesis enzyme expression•The LXR inverse agonist SR9243 inhibits glycolysis and lipogenesis in cancer cells•SR9243 induces cancer cell death but is non-toxic to non-malignant cells•SR9243 has therapeutic effects without weight loss, liver toxicity, or inflammation Flaveny et al. design a liver-X-receptor (LXR) inverse agonist SR9243 that induces LXR-corepressor interaction. SR9243 displays broad anti-tumor activity and a favorable safety profile by selectively targeting the Warburg effect and lipogenesis.