1A-116 Rac1 inhibitor as a novel therapeutic agent in aggressive cancer types

MAGGIO, J.; NAZARENO GONZÁLEZ; CARDAMA, G.

Simposio; SISTAM 2018- The Fourth Symposium in Signal Transduction and Molecular Medicine; 2018

Rho GTPases are molecular switches that cycle between an activated GTP-bound state and an inactive GDP-bound state, being Rac1 one of the most studied members. Rac1 GTPase signaling pathway presents a critical role in the regulation of a plethora of cellular functions governing cancer cell behavior, including cell proliferation, migration and apoptosis. Rac1 is involved in every step during cancer progression and new studies highlight the importance of Rac1 pathway activation as an adaptive advantage for cancer cells to survive and acquire resistance to current treatments.Here we show the development of 1A116, a novel rationally designed Rac1 small molecule inhibitor, as a potential new therapeutic agent for the treatment of aggressive cancer types. 1A116 was tested in a panel of 20 different human cell lines and showed antitumor in vitro effect in a range of 10-50 μM. This antiproliferative effect was associated with a modulation of Rac1 signaling pathway. 1A116 was able to modulate glioblastoma cell growth in vitro (72 h, long term and 3D proliferation) and in vivo, showing a significant increase in survival in mice bearing intracranial human glioblastoma tumors treated with 1A116 20 mg/kg/day compared to vehicle-treated group. Additionally, daily i.p treatment with 10 mg/kg 1A116 reduced in vivo tumor growth (growth rate and tumor volume) in a syngeneic mammary carcinoma model. Interestingly, similar results were observed when mice were treated once a week with 1 mg/kg intravenously. These results support 1A-116 as an interesting therapeutic agent for the treatment of cancer indications where Rac1 pathway is hyperactivated, including glioblastoma and breast cancer.