Small Molecules Identified by an In Silico Docking Screen Targeting Anaphase-Promoting Complex/Cyclosome Subunit 1...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Anti-mitotic drugs are crucial cancer therapies.
• Enhancing their efficacy by targeting cell cycle progression is a key strategy.
• The anaphase-promoting complex/cyclosome (APC/C) is a critical regulator of mitosis.

Purpose of the Study:

• To identify small molecules that inhibit the APC/C co-factor CDC20.
• To evaluate the synergistic effects of identified compounds with anti-mitotic drugs in cancer cells.

Main Methods:

• In silico docking screen of 15,000 small molecules against APC1.
• In cellulo bioactivity screening using MDA-MB-231 breast cancer cells.
• Combination treatment with paclitaxel or eribulin, followed by FACS analysis.

Main Results:

• Five small molecules were identified via in silico screening.
• Two compounds with a 2-(trifluoromethyl)quinazolin-4-amine structure enhanced paclitaxel-induced cell death.
• These compounds showed synergistic effects in combination therapy.

Conclusions:

• Identified compounds are promising starting points for developing novel anti-cancer therapeutics.
• Further optimization and target validation are warranted.
• The strategy of targeting APC/C in combination with anti-mitotic drugs shows potential for cancer treatment.