Uncovering α-Selectivity for Liver X Receptor Agonists for Lipotoxic Cancer Therapies
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 <b>40</b> 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.
Authors
- Michael Lämmerhofer (ORCID: https://orcid.org/0000-0002-1318-0974)
- Ramona Rudalska (ORCID: https://orcid.org/0000-0002-1742-0912)
- Pascal Woelffing
- Stephanie R. Ebner
- Júlia G. B. Pedreira (ORCID: https://orcid.org/0000-0002-9762-2986)
- Stefan Laufer (ORCID: https://orcid.org/0000-0001-6952-1486)
- Petr Pávek (ORCID: https://orcid.org/0000-0001-8769-4196)
- Lucie Smutná (ORCID: https://orcid.org/0000-0002-3941-4193)
- Lars Zender (ORCID: https://orcid.org/0000-0001-7626-2849)
- Azam Rashidian
- Benedikt Masberg (ORCID: https://orcid.org/0000-0003-2041-4983)
- Jenni Küblbeck (ORCID: https://orcid.org/0000-0002-6439-4403)
- Daniel Dauch (ORCID: https://orcid.org/0000-0002-9805-5784)
- Thales Kronenberger (ORCID: https://orcid.org/0000-0001-6933-7590)
- Annachiara Esposito (ORCID: https://orcid.org/0000-0002-5017-1954)
- Moritz Schwarz (ORCID: https://orcid.org/0009-0002-8874-3724)
- Ekaterina Schevchenko
Institutions
- University of Eastern Finland (FI)
- German Cancer Research Center (DE)
- Charles University (CZ)
- Heidelberg University (DE)
- Finland University (FI)
- German Center for Infection Research (DE)
- Institute for Molecular Science (JP)
- Guided Therapeutics (United States) (US)
- University of Hradec Králové (CZ)
- University of Tübingen (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-03-24
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02712
- Citations
- 4
- Primary Topic
- Cholesterol and Lipid Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 8.03