2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2025 Feb 5:283:117136. doi: 10.1016/j.ejmech.2024.117136.
Lorenzo Pontini 1,  Tommaso Angelini 1,  Pietro Palazzoli 1,  Daniela Maggioni 2,  Gianluca Giorgi 3,  Laura Raccosta 2,  Giuseppe Damiano 2,  Valerio Mammoli 4,  Niccolò Fontana 4,  Vincenzo Russo 5,  Maura Marinozzi 6
Affiliations

Affiliations

  • 1 Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Via del Liceo, 1-06123, Perugia, Italy.
  • 2 Immuno-Biotherapy of Melanoma and Solid Tumors Unit, Division of Experimental Oncology, IRCCS Scientific Institute San Raffaele, via Olgettina, 58-20132, Milan, Italy.
  • 3 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via A. Moro, 53100, Siena, Italy.
  • 4 Center for Drug Discovery and Development-DMPK, Aptuit, an Evotec Company, Via A. Fleming 4, 37135, Verona, Italy.
  • 5 Immuno-Biotherapy of Melanoma and Solid Tumors Unit, Division of Experimental Oncology, IRCCS Scientific Institute San Raffaele, via Olgettina, 58-20132, Milan, Italy. Electronic address: russo.vincenzo@hsr.it.
  • 6 Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Via del Liceo, 1-06123, Perugia, Italy. Electronic address: maura.marinozzi@unipg.it.
PMID: 39671877 DOI: 10.1016/j.ejmech.2024.117136
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.

Keywords

Anticancer agents; LXR antagonist; Oxysterol derivatives; Semi-synthesis of steroids.

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