Discovery of Pyroptosis-inducing Drugs and Antineoplastic Activity based on the ROS/ER Stress/Pyroptosis Axis

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Pyroptosis is a promising cancer treatment mechanism.
• Natural products are key in anticancer drug discovery.
• Medicine food homologous natural products (MFHNP) offer safety advantages.

Purpose of the Study:

• To develop a potent pyroptosis inducer by modifying chalcone structures.
• To enhance antitumor activity of natural product-based compounds.

Main Methods:

• Synthesized chalcone analogs and screened for anticancer activity.
• Utilized MTT assays and morphological analysis for pyroptosis detection.
• Employed quantitative structure-activity relationship (QSAR) modeling and in vitro/in vivo studies.

Main Results:

• The α, β-unsaturated ketone moiety is crucial for pyroptosis induction.
• Compound 7 demonstrated significant anticancer activity.
• Compound 7 induced pyroptosis by upregulating CHOP via increased ROS levels.
• Compound 7 suppressed lung cancer xenograft growth.

Conclusions:

• Compound 7 is a promising pyroptosis inducer with antineoplastic activity.
• The ROS/ER stress/pyroptosis axis is a key target for compound 7's action.