Small Molecule Inhibitors of Tyrosine Phosphatase PTP4A3: A Novel Therapeutic Paradigm for Treating Breast Cancer
Abstract
It is estimated that breast cancer will account for 29% of all new cancer diagnoses in women, and it is the second leading cause of cancer-related death for women. Among the different types of breast cancers, triple-negative breast cancer (TNBC) is estimated to account for 15%-20% of all breast cancer diagnoses. Patients diagnosed with triple-negative breast cancer have the worst prognosis of all breast cancer patients, as they lack targeted hormone treatment options; they must rely on invasive surgery, radiation treatment, and/or the use of highly toxic chemotherapy. Hence, the challenge is to address these currently limited medical options by developing a novel, targeted, and less toxic therapeutic to aid in curing patients diagnosed with TNBC. Recent studies have identified the protein tyrosine phosphatase PTP4A3 as an important enzyme that drives TBNC. Based on this finding, it is hypothesized that a small molecule drug that inhibits the cellular activity of PTP4A3 will provide a novel method for more effectively treating and curing patients diagnosed with TBNC. This innovative, collaborative, 3-year proposal unites synthetic medicinal chemistry, computational chemistry and chemical informatics, and cellular biology to develop a recently identified inhibitor of PTP4A3 into a drug-like lead candidate for future testing in animal models of TBNC. The research strategy involves the rational design and synthesis of new compounds that are first tested and optimized for potency and selectivity against the PTP4A3 enzyme alone. Subsequently, the most potent inhibitors of PTP4A3 are tested in different TBNC cancer cell types, and are synthetically optimized to negatively affect TBNC cell function and survival, while having minimal to no effect on normal cells. Finally, the most efficacious inhibitors from the cell testing phase are examined for pharmacological properties that are important for drug-likeness. Specifically, evaluation for metabolism and clearance in liver cells, and the binding of plasma proteins in blood serum will be examined. Subsequently, the compounds will be synthetically modified to address any problems associated with metabolism, clearance, and plasma protein binding. The final deliverables will be two to three drug-like PTP4A3 inhibitor candidates for future testing in animal models of TBNC. Successful outcomes from the proposed studies will provide the framework for the evolution of a completely new drug-based paradigm to provide a better treatment option for patients diagnosed with TBNC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810012
Entities
People
- John S. Lazo
Organizations
- United States Army
- University of Virginia