Smac/DIABLO was recently discovered as a potent pro-apoptotic protein released from mitochondria. Smac functions as an endogenous antagonist for the Inhibitors of Apoptosis Proteins (lAPs) by binding to the BIR3 domain of X-linked lAP (XIAP) and other lAP proteins and displace caspase-9 from this site. High resolution 3D structures of Smac in complex with the BIR3 domain of XIAP showed that the interaction between them is mediated by only four Smac residues at its N-terminus and a small but well-defined binding groove in the XIAP BIR3 domain, which is suitable for designing small molecule inhibitors. Several recent studies have shown that short Smac peptides (4-8 residues) tethered to a carrier peptide for intra-cellular delivery are effective to overcome apoptosis-resistance of cancer cells in vitro and in vivo by directing targeting lAP proteins, while having no toxicity to normal tissues or to animals. Hence, Smac mimetics that bind to the BIR3 domain in XlAP where Smac and caspase-9 bind may have great therapeutic potential to be developed as an entirely new class of anticancer drugs through overcoming apoptosis-resistance of cancer cells as mediated by lAP protein overexpression. In this project, we propose to design, synthesize and characterize highly potent Smac peptido-mimetics and nonpeptidic mimetics with much improved cell permeability over Smac peptides through the following Specific Aims:
Aim 1. (a). Structure-based design of Smac peptido-mimetics and nonpeptidic mimetics based upon the published high-resolution experimental structures of Smac in complex with XlAP BIR3. (b). Determination of high-resolution structures of several most potent Smac mimetics through X-ray crystallography.
Aim 2. Chemical synthesis of these Smac mimetics designed in Aim 1.
Aim 3. (a). Determination of the binding affinities of these Smac mimetics to the BIR3 domain of XIAP by the fluorescence polarization-based method; (b). Conclusive confirmation of the binding of the most potent Smac mimetics to the XlAP BIR3 protein by NMR methods.
Aim 4. Investigation of the activity, specificity and molecular mechanisms of action of the most potent Smac mimetics. Designing highly potent and cell-permeable Smac mimetics is a new and exciting area of research. Our current proposed research represents the first but an essential step toward our long-term goal of developing a novel anticancer drug through targeting apoptosis-resistance in cancer cells mediated by lAP proteins.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109025-02
Application #
6908072
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Lees, Robert G
Project Start
2004-07-01
Project End
2008-04-30
Budget Start
2005-07-01
Budget End
2006-04-30
Support Year
2
Fiscal Year
2005
Total Cost
$282,285
Indirect Cost
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 TNFα expression and receptor tyrosine kinase signaling. Cancer Res 72:1229-38
Wang, Shaomeng; Bai, Longchuan; Lu, Jianfeng et al. (2012) Targeting inhibitors of apoptosis proteins (IAPs) for new breast cancer therapeutics. J Mammary Gland Biol Neoplasia 17:217-28
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
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. (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

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