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Characterization of Rac/Cdc42 Inhibitors as Anti‐cancer Compounds

Metastatic breast cancer continues to be the primary cause of cancer‐related death in women, needing targeted therapies to inhibit this process. Therefore, we are designing small molecule inhibitors to specifically block the metastatic phase, focusing on the Rho GTPases Rac1 and Cdc42. These close homologs direct the actin cytoskeletal changes required for cell migration/invasion, driving the first steps of metastasis. Rho GTPases are activated by Guanine Nucleotide Exchange Factors (GEF), which promote the exchange of GDP to GTP. We have designed the molecule Ehop‐016, a carbazole derivative, to inhibit Rac1 at an IC50 of 1.1 uM by disrupting the interaction of the GEF Vav2 with Rac1. Based on this molecule, we designed a more potent inhibitor, MBQ‐167, to block both Rac1 and Cdc42 at IC50s 103 nM and 78 nM, respectively,in human HER2 (+) breast cancer cells and triple‐negative breast cancer cells. Moreover, MBQ‐167 inhibits tumor growth and metastasis by ~90% in pre‐clinical mouse models of breast cancer. MBQ‐167 also has a different mechanism of inhibition to EHop‐016 by direct inhibition of GTP/GDP binding. We hypothesized that by designing stronger inhibitors based on MBQ‐167 structure with drug‐like properties, we could achieve an improved inhibition for Rac1 and Cdc42, as well as achieve different specificities against the numerous oncogenic GEFs that regulate cancer malignancy. Thus, we synthesized a panel of derivatives, maintaining 9‐ethyl‐3‐(1H‐1,2,3‐triazol‐1‐yl)‐9H‐carbazole as the core for each derivative. HER2 (+) breast cancer cells were treated with 500 nM of the derivatives for 72 hrs. The CellTiter 96 Non‐Radioactive Cell Proliferation Assay was used to analyze cell viability by quantifying both attached and detached cells in the same well. Results show that MBQ‐167 derivatives decreased cell viability to various degrees. Therefore, we have demonstrated that small structural modifications of MBQ‐167 can affect the cytotoxic activity of carbazole derivatives with potential as anti‐cancer drugs, and as tools to block Rac/Cdc42 activities in biological systems.