Metastasis is a key factor for poor prognosis in cancer patients. Ovarian cancer is the fifth most common gynecological cancer causing significant mortality among women. Breast cancer is the most common invasive cancer in women and the second-most common cause of death in American women. Triple negative breast cancer tends to be both unresponsive to chemotherapy and more aggressive than other types of breast cancer. New therapies to prevent spread of these cancer types are urgently needed. There is recent scientific evidence that both migration and cytoskeleton rearrangement associated with metastases of these cancer types is controlled by a specific protein kinase. By using a rational design approach that combines structural protein kinase information and optimal ADME properties, we have discovered a novel series of potent kinase inhibitors. The goal of this work is to optimize our newly discovered series of inhibitors as agents to prevent metastasis in triple negative breast cancer and ovarian cancer. Preliminary data indicates that the lead is effective in inhibiting the migration of triple negative breast and ovarian cancer cells. In this work, new compounds will be identified utilizing our assay cascade combining in vitro receptor pharmacology and cell mobility assays to select lead molecules. Candidate ligands will be designed and synthesized using a series of recognized approaches in medicinal chemistry. Our study will open up a new avenue of target-specific drug development for specific types of breast cancer patients such as TNBC and ovarian cancer.
Triple negative breast cancer (TNBC) is a type of breast cancer that is negative for the estrogen receptor (ER), progesterone receptor (PR) and the human epidermal growth factor receptor 2 (Her2). Since hormonal therapy does not work for TNBC, other anti-tumor agents (such as cisplatin) have been attempted, but with little success. Ovarian cancer (OC) is the fifth most common gynecological cancer causing significant mortality among women. New therapies to prevent spread of these cancer types are urgently needed. In this proposal, we will develop novel small molecule kinase inhibitors capable of blocking the ability of these cancers to metastasize, and evaluate them as novel anti-cancer drug candidates for human OC and TNBC patient treatment.