Novel Small-Molecule Inhibitors of Rac1 in Metastatic Breast Cancer

Abstract

A novel inhibitor of Rac activity based on the structure of the established Rac/Rac-GEF inhibitor NSC23766 is discloses. The compound EHop-016, with an IC50 of 1.1 μM, is a 100-fold more efficient inhibitor of Rac activity than NSC23766. EHop-016 is specific for Rac1 and Rac3 at concentrations ≦5 mM. At higher concentrations, EHop-016 inhibits the close homolog Cdc42. In MDA-MB-435 cells, EHop-016 (≦5 mM) inhibits the association of the Rac-GEF Vav2 with a nucleotide-free Rac1(G15A), which has a high affinity for activated GEFs. EHop-016 does not affect the association of the Rac-GEF Tiam-1 with Rac1(G15A) at similar concentrations. EHop-016 also inhibits the Rac activity of MDA-MB-231 metastatic breast cancer cells and reduces Rac-directed lamellipodia formation in both cell lines. EHop-016 decreases Rac-downstream effects of p21-activated kinase (PAK)1 activity and directed migration of metastatic cancer cells. At low concentrations (<5 μM), EHop-016 does not affect cell viability.

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