Benzothiazole Amides as TRPC3/6 Inhibitors for Gastric Cancer Treatment

Area of Science:

• Medicinal Chemistry
• Molecular Pharmacology
• Cancer Biology

Background:

• Transient receptor potential canonical channel 6 (TRPC6) is implicated in various malignant tumors.
• A scarcity of potent TRPC6 antagonists limits therapeutic development.
• High-throughput screening identified benzothiazole amide derivative 1a as a TRPC6 activator.

Purpose of the Study:

• To design and synthesize novel benzothiazole amide derivatives as TRPC6 modulators.
• To investigate the structure-activity relationship governing TRPC6 agonistic/antagonistic activity.
• To evaluate the anti-cancer potential of synthesized compounds against gastric cancer cells.

Main Methods:

• Cell-based high-throughput screening for TRPC6 modulators.
• Design and synthesis of a series of benzothiazole amide derivatives.
• Molecular docking analyses to predict binding conformations and activities.
• In vitro assays to determine inhibitory potency (IC50) against TRPC channels.
• Evaluation of anti-gastric cancer activity and effects on cell invasion and migration.

Main Results:

• Compound 1a was identified as a TRPC6 activator.
• Docking analyses suggested that binding conformation dictates TRPC6 activity (agonist vs. antagonist).
• Compound 1s, featuring a tetrahydronaphthalene group, fits the antagonist-bound TRPC6 conformation.
• Compound 1s exhibited potent inhibition of TRPC3 and TRPC6 (IC50 values in the low micromolar range).
• Compound 1s demonstrated significant anti-gastric cancer activity against AGS and MKN-45 cell lines.
• 1s inhibited the in vitro invasion and migration of MKN-45 cells.

Conclusions:

• Benzothiazole amide derivatives can be modulated to act as TRPC6 agonists or antagonists based on their binding conformation.
• Compound 1s is a potent TRPC6 antagonist with promising anti-gastric cancer properties.
• Compound 1s warrants further investigation as a potential therapeutic agent for gastric cancer.