Discovery of 22(S)-23-phenyl-24-norchol-5-en-3β,22-diol (PFM046) as the first-in-class, steroidal, non-sulfated Liver
Lorenzo Pontini1, Tommaso Angelini1, Pietro Palazzoli1
1Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Via del Liceo, 1-06123, Perugia, Italy.
Abstract:
A plethora of studies have demonstrated the crucial role played by Liver X Receptors (LXRs) in cancer. However, whether LXRs activation results in pro-versus anti-tumor effects is still matter of debate. Recently, we have reported the ability of 22(S)-hydroxycholesterol-3-sulfate (PFM037) to antagonize LXRα activity, and, at the same time, its capability to improve in-vivo anti-tumor immune responses. Herein we report the first study aimed at the definition of structure-activity relationships of PFM037. Successfully, we identified 22(S)-23-phenyl-24-norchol-5-en-3β,22-diol (PFM046) as a more potent LXRs antagonist than PFM037. PFM046 showed a peculiar LXR target gene expression profile, being able, as expected for an antagonist, to suppress SCD1 and FASN expression, while surprisingly maintaining the ability to upregulate ABCA1 gene, as typical for an agonist. PFM046 showed a remarkable antitumor activity in two both in vitro-and in-vivo mouse models, highlighting the high potential of LXRs antagonists in oncological applications.
Insights
Liver X Receptors (LXRs) play a role in cancer, but their effects are debated. A new compound, PFM046, acts as a potent LXR antagonist, showing significant antitumor activity in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Liver X Receptors (LXRs) are implicated in cancer, with debated pro- or anti-tumor roles.
- Previous research identified 22(S)-hydroxycholesterol-3-sulfate (PFM037) as an LXRα antagonist that enhances anti-tumor immunity.
Purpose of the Study:
- To define the structure-activity relationships of PFM037.
- To identify novel and more potent LXR antagonists for cancer therapy.
Main Methods:
- Synthesis and characterization of PFM037 derivatives.
- Assessment of LXR antagonist potency and target gene modulation (SCD1, FASN, ABCA1).
- Evaluation of in vitro and in vivo antitumor activity in mouse models.
Main Results:
- 22(S)-23-phenyl-24-norchol-5-en-3β,22-diol (PFM046) was identified as a potent LXR antagonist, superior to PFM037.
- PFM046 exhibited a unique gene expression profile, suppressing SCD1/FASN while upregulating ABCA1.
- PFM046 demonstrated significant antitumor efficacy in both in vitro and in vivo mouse cancer models.
Conclusions:
- PFM046 represents a promising novel LXR antagonist.
- LXRs antagonists hold significant potential for oncological applications.
- The unique activity profile of PFM046 warrants further investigation for cancer treatment.
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