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Harnessing the Estradienone Scaffold to Develop Dual GPBAR1 and LIFR Modulators for Liver Fibrosis
Rosa De Gregorio1, Federica Moraca1, Pasquale Rapacciuolo1
1Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, I-80131 Naples, Italy.
Abstract:
Fibrosis is a pathological process characterized by excessive deposition of the extracellular matrix (ECM) within tissues. Chronic fibrotic disorders involving the lungs, liver, intestine, and kidneys represent a major cause of morbidity and mortality and remain a major unmet therapeutic need. In the liver, the development of pathological ECM depends on the activation of key cell targets, i.e., the hepatic stellate cells (HSC). HSCs express the leukemia inhibitory factor receptor (LIFR), which promotes fibrosis, and a bile acid-activated receptor, GPBAR1, which attenuates HSC activation. Herein, we report the design and synthesis of a new class of 4,9-estradien-3,17-dione derivatives acting as dual LIFR inhibitors and GPBAR1 agonists. In silico and pharmacological characterization of these dual modulators led to the identification of compound 2o as a first-in-class LIFR/GPBAR1 modulator that reverses liver fibrosis in vitro and in vivo. These findings demonstrate the therapeutic potential of LIFR/GPBAR1 hybrid molecules in human fibrotic disorders.
Insights
Researchers developed novel compounds targeting both LIFR and GPBAR1 to combat fibrosis. Compound 2o, a dual inhibitor/agonist, successfully reversed liver fibrosis in preclinical models, offering new therapeutic potential.
Area of Science:
- Biochemistry
- Pharmacology
- Molecular Biology
Background:
- Fibrosis, characterized by excessive extracellular matrix (ECM) deposition, is a significant cause of morbidity and mortality in organs like the liver.
- Hepatic stellate cells (HSCs) are key targets in liver fibrosis, expressing LIFR (promotes fibrosis) and GPBAR1 (attenuates HSC activation).
Purpose of the Study:
- To design and synthesize novel 4,9-estradien-3,17-dione derivatives as dual inhibitors of LIFR and agonists of GPBAR1.
- To identify a first-in-class modulator targeting both LIFR and GPBAR1 for potential anti-fibrotic therapy.
Main Methods:
- In silico modeling and computational analysis.
- Chemical synthesis of 4,9-estradien-3,17-dione derivatives.
- In vitro and in vivo pharmacological characterization of synthesized compounds.
Main Results:
- Successful design and synthesis of novel dual LIFR inhibitors and GPBAR1 agonists.
- Identification of compound 2o as a potent LIFR/GPBAR1 modulator.
- Demonstration that compound 2o reverses liver fibrosis both in vitro and in vivo.
Conclusions:
- LIFR/GPBAR1 hybrid molecules represent a promising therapeutic strategy for fibrotic disorders.
- Compound 2o exhibits significant potential for treating liver fibrosis and potentially other fibrotic conditions.
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