Mechanisms of p27Kipl Proteolysis in Cancer Cells

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DESCRIPTION (provided by applicant): The cyclin kinase inhibitor p27Kip1 is a potent inhibitor of cell proliferation and plays important roles in the suppression of tumorigenesis in a variety of human cancers. It has been very well established that abnormally low amounts of p27Kip1 is associated with numerous human tumors. Unlike many other tumor suppressor proteins such as p53, inactivation of p27Kip1 by mutations is very rare in human cancers instead low levels of p27Kip1 expression is primarily caused by excessive degradation by a ubiquitin-mediated pathway. Restoring p27Kip1 expression in tumor cells by introducing non-degradable p27Kip1 or simply overexpression often induces tumor apoptosis or tumor cell death. Thus in vitro and in vivo studies support the concept that stabilization of p27Kip1 in tumor cells may have therapeutic potentials to combat human cancers. Small molecule compounds generated by synthetic chemical routes continue to represent the most effective strategy for targeted therapeutics and cytotoxic drugs. By screening a small molecule library of ~6000 compounds, we discovered two promising small molecule compounds that perturb a key molecular interaction critical for p27Kip1 degradation. These compounds also stabilize p p27Kip1 in tumor cell lines. We propose to perform systematic lead compound evolution and optimization and determine chemotherapeutic efficacy of our optimized lead compounds to inhibit breast cancer growth and metastasis in mice. PUBLIC HEALTH RELEVANCE: The goal of this competitive revision is to perform systematic lead compound evolution and optimization of small molecule compound disovered from our high throughput screen for anti-tumor activity. We will also evaluate the chemotherapeutic efficacy of our optimized lead compounds to inhibit breast cancer growth and metastasis in mice.