Novel inhibitors of Rac1 in metastatic breast cancer

Rho family GTPases are molecular switches that control signaling pathways regulating a myriad of cellular functions. Rac1, a Rho family member, plays a critical role in several aspects of tumorigenesis, cancer progression, invasion, and metastasis. Rac proteins are not mutated in most invasive human cancers but are found to be overactive or over-expressed. Since Rho GTPases are activated by guanine nucleotide exchange factors (GEFs), inhibition of the interaction of Rac with its GEFs is a targeted strategy for blocking Rac activation.

The IC50 of NSC23766, an inhibitor of the interaction of Rac1 with a subset of GEFs, is too high for therapeutic use and more efficacious inhibitors are desired. Therefore, we initiated the synthesis of new derivatives of NSC23766 with modifications of the substituents connected to the central pyrimidine ring, and tested their Rac1 inhibitory activity.

Several of the NSC23766 derivatives were shown to inhibit Rac1 activity of cancer cells with higher efficiency (20-50% more) than NSC23766. The new compounds are not toxic to normal mammary epithelial cells and are more efficient (60-70%) than NSC23766 in inhibiting cell migration and reducing cell spreading and extension of lamellipodia, cell functions regulated by Rac that contribute to cancer invasion.

Based on the results, we conclude that the novel compounds show promise of further development as small molecule inhibitors of invasive breast cancer progression.