Last update 01 Nov 2024

FXR x LIFR

Last update 01 Nov 2024

Basic Info

Related Targets

FXRLIFR

Drugs associated with FXR x LIFR

FXR/LIFR modulators(Università degli Studi di Napoli Federico II)

Target

FXR x LIFR

Mechanism

FXR agonists [+1]

Active Org.

Università degli Studi di Napoli Federico II

Originator Org.

Università degli Studi di Napoli Federico II

Active Indication

Fibrosis, Liver

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with FXR x LIFR

100 Translational Medicine associated with FXR x LIFR

0 Patents (Medical) associated with FXR x LIFR

Literatures (Medical) associated with FXR x LIFR

24 Oct 2024·Journal of Medicinal Chemistry

Design, Synthesis, and Pharmacological Evaluation of Dual FXR-LIFR Modulators for the Treatment of Liver Fibrosis

Article

Author: Bordoni, Martina ; Massa, Carmen ; Morretta, Elva ; Zampella, Angela ; Finamore, Claudia ; Catalanotti, Bruno ; Spinelli, Lucio ; Cassiano, Chiara ; Lupia, Antonio ; Biagioli, Michele ; Fiorillo, Bianca ; Monti, Maria Chiara ; Sepe, Valentina ; Fiorucci, Stefano ; Moraca, Federica ; Rapacciuolo, Pasquale ; Urbani, Ginevra ; Marchianò, Silvia ; Giorgio, Cristina Di

Although multiple approaches have been suggested, treating mild-to-severe fibrosis in the context of metabolic dysfunction associated with liver disease (MASLD) remains a challenging area in drug discovery. Pathogenesis of liver fibrosis is multifactorial, and pathogenic mechanisms are deeply intertwined; thus, it is well accepted that future treatment requires the development of multitarget modulators. Harnessing the 3,4,5-trisubstituted isoxazole scaffold, previously described as a key moiety in Farnesoid X receptor (FXR) agonism, herein we report the discovery of a novel class of hybrid molecules endowed with dual activity toward FXR and the leukemia inhibitory factor receptor (LIFR). Up to 27 new derivatives were designed and synthesized. The pharmacological characterization of this series resulted in the identification of 3a as a potent FXR agonist and LIFR antagonist with excellent ADME properties. In vitro and in vivo characterization identified compound 3a as the first-in-class hybrid LIFR inhibitor and FXR agonist that protects against the development of acute liver fibrosis and inflammation.

01 Jan 2023·Frontiers in oncology

Discovery of BAR502, as potent steroidal antagonist of leukemia inhibitory factor receptor for the treatment of pancreatic adenocarcinoma.

Article

Author: Ricci, Patrizia ; Fiorucci, Stefano ; Zampella, Angela ; Massa, Carmen ; Distrutti, Eleonora ; Rosselli, Rosalinda ; Bellini, Rachele ; Rapacciuolo, Pasquale ; Urbani, Ginevra ; Lupia, Antonio ; Morretta, Elva ; Moraca, Federica ; Di Giorgio, Cristina ; Marchianò, Silvia ; Biagioli, Michele ; Sepe, Valentina ; Monti, Maria Chiara ; Bordoni, Martina ; Catalanotti, Bruno

IntroductionThe leukemia inhibitory factor (LIF), is a cytokine belonging to IL-6 family, whose overexpression correlate with poor prognosis in cancer patients, including pancreatic ductal adenocarcinoma (PDAC). LIF signaling is mediate by its binding to the heterodimeric LIF receptor (LIFR) complex formed by the LIFR receptor and Gp130, leading to JAK1/STAT3 activation. Bile acids are steroid that modulates the expression/activity of membrane and nuclear receptors, including the Farnesoid-X-Receptor (FXR) and G Protein Bile Acid Activated Receptor (GPBAR1).MethodsHerein we have investigated whether ligands to FXR and GPBAR1 modulate LIF/LIFR pathway in PDAC cells and whether these receptors are expressed in human neoplastic tissues.ResultsThe transcriptome analysis of a cohort of PDCA patients revealed that expression of LIF and LIFR is increased in the neoplastic tissue in comparison to paired non-neoplastic tissues. By in vitro assay we found that both primary and secondary bile acids exert a weak antagonistic effect on LIF/LIFR signaling. In contrast, BAR502 a non-bile acid steroidal dual FXR and GPBAR1 ligand, potently inhibits binding of LIF to LIFR with an IC₅₀ of 3.8 µM.DiscussionBAR502 reverses the pattern LIF-induced in a FXR and GPBAR1 independent manner, suggesting a potential role for BAR502 in the treatment of LIFR overexpressing-PDAC.

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