Hepatocellular carcinoma (HCC) is one of the most frequent causes of cancer-related deaths worldwide. We recently showed that pharmacologically induced lipotoxicity represents a promising therapeutic strategy for the treatment of HCC. Synthetic LXRα agonists induce the production of toxic saturated fatty acids in tumor cells. When combined with DFG-out Raf inhibitors, which block fatty acid desaturation by inducing proteasomal degradation of stearoyl-CoA desaturase (SCD1), LXRα activation can trigger lipotoxicity-induced cancer cell death. However, the clinical translation of this therapeutic strategy is limited by the lack of specific LXRα agonists for clinical use. Here, we have developed a series of promising maleimide LXR agonists with increased potency for LXRα and enhanced specificity. Our agonist frontrunner 40 shows high selectivity for LXRα and strong therapeutic efficacy in HCC organoids, therefore illustrating a strong potential for advancing this lipotoxic treatment strategy to clinical application.

A 1 Virtanen Institute for Molecular Sciences University of Eastern Finland P O Box 1627 Kuopio FI 70210 Finland

Department of Medical Oncology and Pneumology University Hospital Tuebingen Otfried Mueller Strasse 14 Tuebingen 72076 Germany

Department of Pharmaceutical and Medicinal Chemistry Institute of Pharmaceutical Sciences University of Tuebingen Auf der Morgenstelle 8 Tuebingen 72076 Germany

Department of Pharmacology and Toxicology Faculty of Pharmacy in Hradec Kralove Charles University Akademika Heyrovskeho 1203 Hradec Kralove 500 05 Czech Republic

German Cancer Research Consortium Im Neuenheimer Feld 280 Heidelberg 69120 Germany

IFIT Cluster of Excellence EXC 2180 'Image Guided and Functionally Instructed Tumor Therapies' University of Tuebingen Tuebingen 72076 Germany

Partner site Tuebingen German Center for Infection Research Elfriede Aulhorn Str 6 Tuebingen 72076 Germany

Pharmaceutical Analysis Institute of Pharmaceutical Sciences Eberhard Karls University of Tuebingen Auf der Morgenstelle 8 Tuebingen 72076 Germany

School of Pharmacy Faculty of Health Sciences University of Eastern Finland P O Box 1627 Kuopio FI 70210 Finland

Tuebingen Center for Academic Drug Discovery and Development Auf der Morgenstelle 8 Tuebingen 72076 Germany

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