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Novel Rac Inhibitors as Targeted Therapeutics for Metastatic Breast Cancer

Metastatic disease is the primary cause of breast cancer mortality, due to the lack of effective therapy. The Rho GTPase Rac is integral for the promotion of cancer cell migration/invasion, proliferation, and survival. Since metastatic breast cancers often overexpress or exhibit high Rac activity, inhibition of Rac is a viable strategy against metastatic cancer. Recently, we characterized EHop‐016, a small molecule that inhibits Rac activity of metastatic breast cancer cells with an IC50 of 1 μM. EHop‐016, which is 10–100 times more active than previously available Rac inhibitors, inhibits the activity of the Rac downstream effector p21 activated kinase (PAK), lamellipodia extension, and cell migration of metastatic breast cancer cells. Moreover, EHop‐016 at ≥ 25 mg/kg Body Weight (BW) significantly reduced tumor growth, metastasis, and angiogenesis in a mouse model. However, our recent pharmacokinetic study of EHop‐016 in a mouse model demonstrated that its bioavailability should to be improved for further pharmacological development. Our hypothesis is that improvement of the EHop‐016 structure will provide probes with increased potency against Rac and improved bioavailability. Herein we have tested several Ehop‐016 derivatives for their effects on breast cancer cell viability, cell migration, and Rac activation. Using MTT assays we found that the Ehop‐016 derivatives, HV‐107 and HV‐118, significantly inhibit the viability of metastatic breast cancer cell lines MDAMB‐231 and MDA‐MB‐435; while presenting minimal toxicity towards non‐cancerous mammary epithelial cells. The effects of HV‐107 and HV‐118 on the inhibition of Rac activation were tested by ELISA‐based Rac activity assays and pulldown assays. Results show that at 250 nM, HV‐107 inhibits Rac activation by 55%, whereas HV‐118 has a similar effect at 100 nM in MDA‐MB‐231 and MDA‐MB‐435 cells. Moreover, using transwell assays we studied the effects of both Rac inhibitors in metastatic breast cancer cell migration and observed a significant reduction. Finally, we tested HV‐107 in a mouse model of metastatic breast cancer and found a 25% reduction in tumor growth in mice treated with 5 mg/kg BW HV‐107. Taken together, our findings suggest HV‐107 and HV‐118 as promising Ehop‐016 derivatives with potential as anti‐metastatic agents, that should be further characterized.