Abstract 4185: The novel Rac inhibitor HV-107 as a potential therapeutic for metastatic breast cancer

Breast cancer is the first cause of death in women globally. Metastatic breast cancer, which occurs when cancer cells migrate from the primary tumor and establish in distant organs, is estimated to affect more than a quarter of a million of women in the US. Regrettably, metastatic breast cancer still lacks effective treatment and remains the principal cause of breast cancer mortality. Therefore, it is imperative to develop new and more effective strategies to inhibit metastasis. A promising target for anti-metastatic cancer therapy is the Rho GTPase Rac because it plays a key role in the regulation of cellular adhesion, migration, proliferation and survival; processes which promote tumorigenesis and metastasis. Recently, our group developed Ehop-016, a small molecule that inhibits Rac in metastatic breast cancer cells with an IC50 of 1µM and reduces the activity of its downstream effector p21-activated kinase (PAK). Ehop-016 also inhibits tumor growth, angiogenesis, and metastasis in a mouse model of metastatic breast cancer. However, its relative bioavailability is moderate and should be further improved. Therefore, in an effort to find a compound with greater inhibitory capacity and bioavailability, we tested several Ehop-016 derivatives for their activity against Rac and their toxicity towards metastatic breast cancer cells. Using Rac pulldown assays we show that HV-107 at 250nM inhibits Rac activation by 55% in MDA-MB-231 and MDA-MB-435 metastatic breast cancer cells. The effects of HV-107 on cell viability were tested by MTT assays and our results indicate HV-107 at ≥500nM significantly inhibits metastatic breast cancer cell viability, while showing minimal toxicity towards non-cancerous mammary epithelial cells. We also measured caspase 3 activity, in order to evaluate apoptosis as a potential mechanism of HV-107-induced cell death. Our results show HV-107 at 1000nM causes a significant 1.5 fold increase in caspase 3 activity in MDA-MB-231 cells, indicating HV-107 affects cell viability by inducing apoptosis. 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 5mg/kg BW HV-107. Taken together, our results suggest HV-107 is approximately four times more efficient than the parent compound Ehop-016 and has potential as anti-breast cancer metastasis therapeutic. This study was supported by awards from the Susan Komen for the Cure, NIH/NIMHHD U54MD008149, and the Puerto Rico