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Research Grants Awarded
Design, Synthesis and Evaluation of XIAP inhibitors as a Novel Therapy for the Treatment of Human Breast Cancer
Most of the current chemotherapeutic agents work by indirectly inducing programmed cell death or apoptosis in human cancer cells. The inhibitors of apoptosis proteins (IAPs) are a class of central apoptosis regulators. X-linked IAP (XIAP) is the best characterized IAP family member and is a potent cellular apoptosis inhibitor. Because XIAP blocks apoptosis at the effector phase, a point where multiple signaling pathways converge, strategies targeting XIAP may prove to be especially effective in overcoming resistance of cancer cells to apoptosis. XIAP is widely expressed in human breast cancer tissues and in human breast cancer cell lines such as MDA-MB-231, MCF-7 and MDA-MB-435. Overexpression of XIAP renders cancer cells resistant to a wide variety of therapeutic agents. XIAP thus represents a very attractive molecular target for the design and development of an entirely new class of cancer therapy for treating breast cancer by overcoming resistance of cancer cells to chemotherapeutic agents. XIAP contains three baculoviral IAP repeat (BIR) domains. Its BIR2 domain, together with the linker before the BIR2 domain, binds to effector caspases-3 and -7 and inhibits their activity and its BIR3 domain binds to and inhibits an initiator caspase-9. Binding of XIAP to these caspases efficiently inhibits their activities for execution of apoptosis. We hypothesize that small-molecule inhibitors designed to concurrently target both the BIR2 and BIR3 domains of XIAP will be highly efficient to completely overcome the anti-apoptotic function of XIAP. In this grant proposal, we propose to design, synthesize, characterize and develop potent, cell-permeable bivalent Smac mimetics as a new class of inhibitors of XIAP. Our preliminary results demonstrate that one of our designed bivalent Smac mimetics, SM-164, has a very high affinity to XIAP (IC50 = 2 nM) and is >8000-times more potent than the natural Smac AVPI peptide. SM-164 is highly effective and potent in inhibition of cell growth and induction of apoptosis in human breast cancer cells with high levels of XIAP. In addition, SM-164 has minimal toxicity to normal cells. Our mechanistic studies have provided initial but clear and convincing evidence that SM-164 targets XIAP in cancer cells. These preliminary data provide strong support for our basic hypothesis and design strategy. Based upon the promising preliminary results, we propose to further optimize our lead compound for binding affinity, cellular activity and in vivo antitumor activity and to elucidate the molecular mechanism of action. Our long-term goal is to develop Smac mimetics such as SM-164 as an entirely new type of anticancer therapy for the treatment of human breast cancer. Successfully carried out, we will be able to bring 1-2 of the most promising non-peptidic Smac mimetics into advanced preliclinical development studies for the treatment of human breast cancer.
The recent remarkable success of trastuzumab (Herceptin, for the treatment of Her-2 positive human breast cancer has provided a powerful example that a molecularly targeted therapy can be highly effective against metastatic breast cancer, with fewer side effects than conventional chemotherapy. We have now entered an era of research where drugs are designed to specifically target cancer-causing proteins that are present in high levels in cancer cells but have very low levels in normal cells (molecular target-specific rational drug design). Most of the current chemotherapeutic agents work by indirectly inducing programmed cell death or apoptosis in human cancer cells. Primary or acquired resistance to current therapies remains a major concern in clinical breast oncology and may be caused by defects in apoptosis pathways. The inhibitor of apoptosis proteins (IAPs) is a new class of proteins that inhibits apoptosis and may play an important role in response of cancer to current therapeutic agents and in the development of drug resistance of cancer cells. XIAP (X-linked IAP) is the most potent and best characterized member among all IAPs. We have found that several breast cancer cell lines have high levels of XIAP expression. XIAP overexpression may be an important factor leading to apoptotic resistance in human breast cancer to chemotherapeutic drugs. Thus, design of small molecule inhibitors that bind to XIAP and inhibit its anti-apoptotic function is represents an attractive strategy for the development of an entirely new class of anticancer drug for the treatment of breast cancer by overcoming drug resistance. Using a powerful structure-based design approach, we have designed a class of highly potent and effective small molecule inhibitors that directly bind to XIAP and induce apoptosis in human breast cancer cells. These compounds serve as promising lead compounds for the design and development of potent small molecule inhibitors of XIAP as new anticancer drugs. This proposal focuses on the further optimization and evaluation of these class of compounds. Our ultimate goal is to derive a highly potent XIAP small molecule inhibitor as a novel therapy for the treatment of breast cancer. We plan to accomplish this goal through effective structure-based design and extensive chemical modifications, and biological testing of these novel inhibitors in biochemical, cellular and animal models of human breast cancer. If successfully carried out, it is expected that our integrated, multi-disciplinary team will be able to bring a potent small molecule XIAP inhibitor into advanced preclinical and Phase I clinical trial in the near future for the treatment of prostate cancer. It is predicted that such a drug will have very few side effects and will be particularly effective when used in combination with current therapeutic agents for treating human breast cancer with high levels of XIAP expression by overcoming drug resistance.