The inhibitors of apoptosis proteins (IAPs) are a class of central apoptosis regulators and potent endogenous apoptosis inhibitors. IAP proteins represent new and highly promising molecular targets for anti-cancer drug design aiming at overcoming apoptosis resistance of cancer cells. Smac/DIABLO, a recently identified protein, directly interacts with IAP proteins and functions as a direct endogenous antagonist of IAPs and is a potent pro-apoptotic molecule in cells. Based on high-resolution three-dimensional structures of Smac protein and peptide in complex with X-linked IAP (XIAP), we have recently designed and synthesized a class of potent, non-peptide, cell-permeable, small- molecule Smac mimetics that target two domains of XIAP. Our preliminary data clearly demonstrate that our promising lead compound may have great therapeutic potential for the treatment of human cancer. Our long-term goal is to develop highly potent, small- molecule Smac mimetics as an entirely new type of anti-cancer therapy for the treatment of human cancer. Toward our long-term goal, we will perform the following three Specific Aims in this grant.
Specific Aim 1 : To perform in vivo studies to determine the toxicity, pharmacokinetics and anti-tumor activity and mechanism of action of the most promising Smac mimetics in animal models of human cancer.
Specific Aim 2 : To design, synthesize novel and potent non-peptide Smac mimetics based upon the promising lead compound;
Specific Aim 3. (a). To determine their binding affinities to IAP proteins;(b) To determine their ability to antagonize the function of IAP proteins in functional assays;(c). To investigate their binding models to IAP proteins.
Specific Aim 4 : (a). To determine their activity in human cancer cells and their selectivity over normal cells. (b). To perform in vitro studies to gain detailed insights into the molecular mechanism of action. Successfully carried out, our proposed research will lead to the development of an entirely new class of molecularly targeted anticancer therapy for the treatment of human cancer by overcoming resistance of cancer cells to apoptosis.

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 #
5R01CA127551-04
Application #
8196806
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Misra, Raj N
Project Start
2009-01-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
4
Fiscal Year
2012
Total Cost
$308,776
Indirect Cost
$107,501
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
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
Lu, Jianfeng; Bai, Longchuan; Sun, Haiying et al. (2008) SM-164: a novel, bivalent Smac mimetic that induces apoptosis and tumor regression by concurrent removal of the blockade of cIAP-1/2 and XIAP. Cancer Res 68:9384-93