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 µM (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.