Inhibitor of apoptosis proteins (IAPs) are a class of key apoptosis regulators. Among these IAP proteins, cellular IAP-1 (cIAP-1) and cellular IAP-2 (cIAP-2) play critical roles in the regulation of death-receptor-mediated apoptosis, and X-linked IAP (XIAP) is a central regulator of both death-receptor-mediated and mitochondria-mediated apoptosis pathways. Because of their central role as apoptosis regulators, XIAP and cIAP-1/2 are promising cancer therapeutic targets. Smac is an endogenous antagonist of these IAP proteins and interacts with them via its AVPI tetrapeptide binding motif. In recent years, intense research efforts have been devoted to the design and development of small molecules known as Smac mimetics, which mimic the AVPI binding motif and function as antagonists of IAP proteins. Smac mimetics are not only capable of sensitizing cancer cells to induction of apoptosis by other therapeutic agents but also are effective as single agents in induction of apoptosis in vitro and in vivo in a subset of cancer cell lines of diverse tumor types. Smac mimetics are considered to have great potential for development as a new class of anticancer drugs. In this R01 competing renewal, we propose to evaluate a novel class of potent, orally active, promising Smac mimetics as new therapies for the treatment of human cancer. Our preliminary data have shown that our promising lead compounds bind to XIAP and cIAP-1/2 with affinities in the low nanomolar range, effectively induce apoptosis in cancer cells, possess minimal toxicity to normal cells and have a cellular mechanism of action highly consistent with targeting IAP proteins for apoptosis induction. One of our lead compounds is highly effective as an oral agent in induction of apoptosis in xenograft tumor tissues and in inhibition of tumor growth in the MDA- MB-231 xenograft model, while showing no toxicity to animals at highly efficacious doses. Our ultimate goal in this project is to develop a highly potent, orally active Smac mimetic as a new therapy for the treatment of human cancer. To maximize the probability of achieving our ultimate goal while using resources most efficiently, we will carry out the following specific Aims:
Aim 1 : Determination of the microsomal and plasma stability in vitro, toxicity and pharmacokinetics in animals, and antitumor activity in multiple xenograft models of human cancer for several of the most promising lead compounds.
Aim 2 : Elucidation, for several of the most promising Smac mimetics, of the cellular mechanism of action for apoptosis induction in cancer cells.
Aim 3 : Structure-based design and synthesis of new analogues based upon the most promising leads to further define the structure-activity relationship for this class of promising Smac mimetics and to identify additional new and superior analogues for in vivo studies.
Aim 4 : For the new analogues obtained in Aim 3, determination of the binding affinities and specificity to IAP proteins, their activity in antagonizing XIAP, their activity in cancer cell lines and selectivity over normal cells. Our preliminary data provide strong support for our central hypothesis, research design and strategy and have laid a solid foundation for the success of this project. Successfully carried out, this project will bring, at a minimum, 1-2 potent, well-characterized, highly optimized, orally active Smac mimetics into advanced preclinical development as a new class of anticancer therapy for the treatment of many types of human cancer.

Public Health Relevance

Cancer is the second leading cause of death in the United State of America. More effective treatments are urgently needed to improve the outcome of millions of cancer patients. This research project aims at the design, synthesis and development of a new class of small-molecule anti-cancer drugs for the treatment of human cancer, including but not limited to breast cancer and prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109025-09
Application #
8598976
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Misra, Raj N
Project Start
2004-07-01
Project End
2014-11-30
Budget Start
2013-12-19
Budget End
2014-11-30
Support Year
9
Fiscal Year
2014
Total Cost
$241,890
Indirect Cost
$84,587
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Bai, Longchuan; Smith, David C; Wang, Shaomeng (2014) Small-molecule SMAC mimetics as new cancer therapeutics. Pharmacol Ther 144:82-95
Sun, Haiying; Lu, Jianfeng; Liu, Liu et al. (2014) Potent and selective small-molecule inhibitors of cIAP1/2 proteins reveal that the binding of Smac mimetics to XIAP BIR3 is not required for their effective induction of cell death in tumor cells. ACS Chem Biol 9:994-1002
Sheng, Rong; Sun, Haiying; Liu, Liu et al. (2013) A potent bivalent Smac mimetic (SM-1200) achieving rapid, complete, and durable tumor regression in mice. J Med Chem 56:3969-79
Peng, Yuefeng; Sun, Haiying; Lu, Jianfeng et al. (2012) Bivalent Smac mimetics with a diazabicyclic core as highly potent antagonists of XIAP and cIAP1/2 and novel anticancer agents. J Med Chem 55:106-14
Bai, Longchuan; McEachern, Donna; Yang, Chao-Yie et al. (2012) LRIG1 modulates cancer cell sensitivity to Smac mimetics by regulating TNF? expression and receptor tyrosine kinase signaling. Cancer Res 72:1229-38
Lu, Jianfeng; McEachern, Donna; Sun, Haiying et al. (2011) Therapeutic potential and molecular mechanism of a novel, potent, nonpeptide, Smac mimetic SM-164 in combination with TRAIL for cancer treatment. Mol Cancer Ther 10:902-14
Sun, Haiying; Liu, Liu; Lu, Jianfeng et al. (2011) Potent bivalent Smac mimetics: effect of the linker on binding to inhibitor of apoptosis proteins (IAPs) and anticancer activity. J Med Chem 54:3306-18
Cai, Qian; Sun, Haiying; Peng, Yuefeng et al. (2011) A potent and orally active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical development for cancer treatment. J Med Chem 54:2714-26
Wang, Shaomeng (2011) Design of small-molecule Smac mimetics as IAP antagonists. Curr Top Microbiol Immunol 348:89-113
Sun, Haiying; Liu, Liu; Lu, Jianfeng et al. (2010) Cyclopeptide Smac mimetics as antagonists of IAP proteins. Bioorg Med Chem Lett 20:3043-6

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