In addition to the unlimited potential of cancer cells for proliferation, a second important contributor to tumor growth and metastasis is the ability of cancer cells to avoid apoptotic cell death. This characteristic may also underlie resistance to chemotherapy. The physiological role of apoptosis in killing abnormally functioning cells can be subverted in cancer cells through genetic lesions that affect key proteins in apoptotic pathways, such as Bcl-2 and p53. Recently, an important family of apoptosis inhibitors, the AIP family of proteins, has been discovered. These proteins may be over expressed, or upregulated, in tumor cells, contributing to resistance to apoptosis. The goal of the present proposal is to discover small molecule antagonists of IAP function that act by inhibiting the BIR domain of the IAP. Inhibition of the BIR domain may produce agents with broad anticancer activity but little effect on normal tissues. These compounds will be used to validate IAP antagonism by BIR inhibition as a target for treating cancer. In addition, they will serve as a starting point for the development of novel cancer therapeutics. Small molecule inhibitors will be rapidly discovered using a proprietary drug discovery technology (TRAP) and profiled in cell-free, cell-based, and in vivo systems to establish their pro-apoptotic and anti-tumor activities. PROPOSED COMMERCIAL APPLICATION: Compounds that can be used to validate BIR inhibition as a successful approach to cancer treatment. Lead compounds the the discovery of novel cancer chemotherapeutics.
