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@ARTICLE{GalvezBPedreira:300125,
author = {J. Galvez B Pedreira and P. Woelffing and M. Schwarz and S.
Ebner and R. Rudalska and B. Masberg and A. Esposito and A.
Rashidian and E. Schevchenko and L. Smutna and P. Pavek and
J. Kublbeck and T. Kronenberger and L. Zender$^*$ and M.
Lämmerhofer and D. Dauch and S. A. Laufer},
title = {{U}ncovering α-{S}electivity for {L}iver {X} {R}eceptor
{A}gonists for {L}ipotoxic {C}ancer {T}herapies.},
journal = {Journal of medicinal chemistry},
volume = {68},
number = {7},
issn = {0095-9065},
address = {Washington, DC},
publisher = {ACS},
reportid = {DKFZ-2025-00623},
pages = {7180-7196},
year = {2025},
note = {2025 Apr 10;68(7):7180-7196},
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.},
cin = {TU01},
ddc = {610},
cid = {I:(DE-He78)TU01-20160331},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40127224},
doi = {10.1021/acs.jmedchem.4c02712},
url = {https://inrepo02.dkfz.de/record/300125},
}