2. Academic Validation
  3. Uncovering α-Selectivity for Liver X Receptor Agonists for Lipotoxic Cancer Therapies

Uncovering α-Selectivity for Liver X Receptor Agonists for Lipotoxic Cancer Therapies

  • J Med Chem. 2025 Apr 10;68(7):7180-7196. doi: 10.1021/acs.jmedchem.4c02712.
Júlia Galvez B Pedreira 1 2,  Pascal Woelffing 2 3,  Moritz Schwarz 1,  Simon Ebner 1,  Ramona Rudalska 2 3,  Benedikt Masberg 4,  Aylin Esposito 2 3,  Azam Rashidian 1,  Ekaterina Schevchenko 1,  Lucie Smutna 5,  Petr Pavek 5,  Jenni Kublbeck 6 7,  Thales Kronenberger 1 6 8,  Lars Zender 2 3 9 10,  Michael Lämmerhofer 4,  Daniel Dauch 2 3 9,  Stefan A Laufer 1 2 8 9
Affiliations

Affiliations

  • 1 Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, University of Tuebingen, Auf der Morgenstelle 8, Tuebingen 72076, Germany.
  • 2 IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tuebingen, Tuebingen 72076, Germany.
  • 3 Department of Medical Oncology and Pneumology, University Hospital Tuebingen, Otfried-Mueller-Strasse 14, Tuebingen 72076, Germany.
  • 4 Pharmaceutical (Bio-)Analysis, Institute of Pharmaceutical Sciences, Eberhard-Karls University of Tuebingen, Auf der Morgenstelle 8, Tuebingen 72076, Germany.
  • 5 Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, Hradec Kralove 500 05, Czech Republic.
  • 6 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, Kuopio FI-70210, Finland.
  • 7 A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, Kuopio FI-70210, Finland.
  • 8 Partner-site Tuebingen, German Center for Infection Research (DZIF), Elfriede-Aulhorn-Str. 6, Tuebingen 72076, Germany.
  • 9 Tuebingen Center for Academic Drug Discovery & Development (TüCAD2), Auf der Morgenstelle 8, Tuebingen 72076, Germany.
  • 10 German Cancer Research Consortium (DKTK), Partner Site Tuebingen, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
PMID: 40127224 DOI: 10.1021/acs.jmedchem.4c02712
Abstract

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.

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