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 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.