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

Although the farnesoid X receptor (FXR) has been regarded as a promising drug target for metabolic diseases as well as anti‐inflammatory, antitumor and antiviral actions, the antagonism by FXR ligands are still underrepresented in current FXR targeted therapies. In this study, we discovered selectiv...

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Published in:ChemMedChem 2022-06, Vol.17 (11), p.e202100778-n/a
Main Authors: Niu, Shuaishuai, Zhang, Guoning, Wang, Na, Lv, Guangyao, Liu, Jinsong, Wang, Hongbo, Fang, Wei‐Shuo
Format: Article
Language:English
Subjects:
Antagonists
Antiproliferation
Cell proliferation
chalcone
FXR antagonist
Inflammation
Lung cancer
Metabolic disorders
Metastases
Non-small cell lung carcinoma
NSCLC
Optimization
Therapeutic targets
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Summary:Although the farnesoid X receptor (FXR) has been regarded as a promising drug target for metabolic diseases as well as anti‐inflammatory, antitumor and antiviral actions, the antagonism by FXR ligands are still underrepresented in current FXR targeted therapies. In this study, we discovered selective FXR antagonists through structure optimization from the polyoxygenated chalcone scaffold. The selective antagonist 6 p [2‐methoxy‐2’‐hydroxy‐4’‐(4’’‐methoxy‐4’’‐oxo‐E‐crotonyl) chalcone] is not only inhibitory toward non‐small‐cell lung cancer (NSCLC) cell proliferation in an FXR‐dependent manner, but is also active in metastasis models. Taken together, this chalcone‐based FXR antagonist has the potential for the targeted therapy of NSCLC in which FXR is highly expressed. A chalcone derivative 6 p was synthesized and identified as an FXR‐selective antagonist, which inhibits non‐small‐cell lung cancer (NSCLC) cell proliferation and migration in an FXR‐dependent manner. It blocks cell cycle in G1 phase and promotes apoptosis. These results demonstrate the potential of this type of FXR antagonist as targeted therapeutics for NSCLC.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.202100778