1. Discovery of 22(S)-23-phenyl-24-norchol-5-en-3β,22-diol (PFM046) as the first-in-class, steroidal, non-sulfated Liver X Receptor antagonist with anticancer activity.
- Author
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Pontini L, Angelini T, Palazzoli P, Maggioni D, Giorgi G, Raccosta L, Damiano G, Mammoli V, Fontana N, Russo V, and Marinozzi M
- Subjects
- Humans, Structure-Activity Relationship, Animals, Mice, Molecular Structure, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Discovery, Drug Screening Assays, Antitumor, Cell Line, Tumor, Liver X Receptors antagonists & inhibitors, Liver X Receptors metabolism, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis
- 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., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Vincenzo Russo reports financial support was provided by Italian Association for Cancer Research. Maura Marinozzi, Vincenzo Russo Laura Raccosta, Lorenzo Pontini has patent LXR ANTAGONISTS pending to European application N. EP23156662.1 (Filing date February 14, 2023) – PCT application n. PCT/EP2024/053768 (Filing date February 14, 2024);. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2025
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