TY  - JOUR
AU  - Galvez B Pedreira, Júlia
AU  - Woelffing, Pascal
AU  - Schwarz, Moritz
AU  - Ebner, Simon
AU  - Rudalska, Ramona
AU  - Masberg, Benedikt
AU  - Esposito, Aylin
AU  - Rashidian, Azam
AU  - Schevchenko, Ekaterina
AU  - Smutna, Lucie
AU  - Pavek, Petr
AU  - Kublbeck, Jenni
AU  - Kronenberger, Thales
AU  - Zender, Lars
AU  - Lämmerhofer, Michael
AU  - Dauch, Daniel
AU  - Laufer, Stefan A
TI  - Uncovering α-Selectivity for Liver X Receptor Agonists for Lipotoxic Cancer Therapies.
JO  - Journal of medicinal chemistry
VL  - 68
IS  - 7
SN  - 0095-9065
CY  - Washington, DC
PB  - ACS
M1  - DKFZ-2025-00623
SP  - 7180-7196
PY  - 2025
N1  - 2025 Apr 10;68(7):7180-7196
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:40127224
DO  - DOI:10.1021/acs.jmedchem.4c02712
UR  - https://inrepo02.dkfz.de/record/300125
ER  -