Structure Modification of FXR Antagonistic Chalcones and Their Inhibitory Effects on NSCLC Cell Proliferation and...

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Pharmacology

Background:

• Farnesoid X receptor (FXR) is a drug target for metabolic diseases, inflammation, and cancer.
• FXR antagonists are underrepresented in current therapeutic strategies.
• Targeting FXR offers potential for novel anti-cancer treatments.

Purpose of the Study:

• To discover selective FXR antagonists using a polyoxygenated chalcone scaffold.
• To evaluate the anti-cancer efficacy of identified FXR antagonists in non-small cell lung cancer (NSCLC) models.
• To explore the potential of chalcone-based FXR antagonists for targeted NSCLC therapy.

Main Methods:

• Structure-based optimization of polyoxygenated chalcones to identify selective FXR antagonists.
• In vitro assays to assess inhibition of NSCLC cell proliferation in an FXR-dependent manner.
• In vivo metastasis models to evaluate the anti-metastatic activity of the lead compound.

Main Results:

• Discovery of selective FXR antagonists derived from the chalcone scaffold.
• Identification of compound 6p [2-methoxy-2'-hydroxy-4'-(4''-methoxy-4''-oxo-E-crotonyl) chalcone] as a potent FXR antagonist.
• Compound 6p demonstrated significant inhibition of NSCLC cell proliferation and activity in metastasis models, dependent on FXR expression.

Conclusions:

• Chalcone-based compounds can be optimized to yield selective FXR antagonists.
• Compound 6p shows promise as a targeted therapeutic agent for FXR-expressing NSCLC.
• FXR antagonism represents a viable strategy for developing novel NSCLC treatments.