Triple-negative breast cancer is the most aggressive subtype with the shortest time to metastasis development. It affects mostly the African-American population, women of younger age, and BCRA1 mutation carriers. Current strategies require the use of a dose-dense multidrug treatment that correlates with high toxicity of therapy. Interestingly, triple-negative breast cancer has a higher response to chemotherapies when compared to other subtypes of breast tumors, especially when combined with whole- brain radiation. Therefore, there is a significant need for new anticancer agents that have activity against triple-negative breast cancer and low toxicity. Because of its ability to cross blood-brain barrier and activity against triple-negative breast cancer, we envision that our lead compound MA371 can have a clinical implication in the treatment of a metastatic form of this disease. Moreover, this compound has lower chance to induce neurotoxicity due to the reduced affinity to serotonin and dopamine receptors. However, our compound has moderate anticancer properties with IC50 of 5.3 ?M (MDA-MB-231, MTT assay) and high lipophilicity that promotes significant accumulation of MA371 in the adipose fat. Therefore, in the aim 1 of our project, we propose chemically modify MA371 in ways that increase its anticancer activity and improves drug-like properties. We will continue monitoring the effect of performed chemical modifications on the ability of molecules to cross the BBB, targeting conservation of this feature of MA371. In the aim 2, we will continue our work towards establishing a molecular target for our lead molecule and its selected analogs (aim 1) and evaluating in vivo efficacy of these compounds using a mice breast tumor metastasis to brain model. The outcome of this project will provide critical information for developing a new type of anticancer agents with the activity against metastatic triple-negative breast cancer, ability to cross the blood-brain barrier and reduced neurotoxicity.
The ability of our lead compound MA371 to inhibit proliferation of metastatic triple-negative breast cancer and to cross blood-brain barrier marks this drug as a promising candidate for anticancer therapy. However, optimization of its moderate selective cytotoxicity against cancer cells and its drug-like properties is required. Here, we propose to modify the structure of this compound in the way it will improve its anticancer properties, maintain the ability to cross the blood-brain barrier and low CNS-related toxicity.