Harnessing the Estradienone Scaffold to Develop Dual GPBAR1 and LIFR Modulators for Liver Fibrosis

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.