# Small Molecules Identified by an In Silico Docking Screen Targeting Anaphase-Promoting Complex/Cyclosome Subunit 1 (APC1) Potentiate Paclitaxel-Induced Breast Cancer Cell Death

## TL;DR

This study identifies small molecules that enhance paclitaxel's effect on breast cancer cells by targeting APC1, a key cell cycle regulator.

## Contribution

The study introduces new small molecules that synergize with paclitaxel to increase breast cancer cell death.

## Key findings

- Two compounds with a 2-(trifluoromethyl)quinazolin-4-amine structure enhanced paclitaxel-induced cell death in breast cancer cells.
- The compounds were identified via in silico docking and validated in cellulo.
- These molecules will guide further optimization and in silico screens for more potent anti-cancer agents.

## Abstract

Delaying mitotic cell cycle progression has been proposed as a strategy to potentiate the effects of anti-mitotic anti-cancer drugs that induce multipolar mitotic spindles. Toward this end, we have performed an in silico docking screen targeting anaphase-promoting complex/cyclosome subunit 1 (APC1) at a conserved 10-amino acid surface site that was modeled to interact via a single hydrogen bond with the essential mitotic anaphase-promoting complex/cyclosome (APC/C) co-factor cell division cycle 20 (CDC20). Five molecules were identified after screening 15,000 small molecules. As a secondary in cellulo bioactivity screening, MDA-MB-231 genomically unstable aneuploid breast cancer cells were exposed to each compound in the absence and presence of 10 nM paclitaxel or 1 nM eribulin, the likely clinically relevant doses of these drugs in these cells. Two of the five compounds, which share a common 2-(trifluoromethyl)quinazolin-4-amine chemical structure, induced elevated levels of cell death in combination with paclitaxel, as observed by fluorescence-activated cell sorting (FACS). These two compounds will now serve as a starting point for further optimization and target validation experiments and for additional in silico screens in search of other chemically related small molecules that display more potent but specific anti-cancer cell effects.