Signal Transducer and Activator of Transcription (STAT) family of proteins were originally discovered in context of cellular responses to cytokines and growth factors. In normal cells, STAT proteins are only transiently activated, which is important for their key roles in physiological process, including cell growth and differentiation, development, inflammation and survival. However, persistent activation of certain members of this family of transcription factors, particularly Stat3, has been found to accompany malignant transformation. In both solid and hematological tumors, including breast cancer, prostate cancer, head and neck squamous cell carcinomas, melanoma and multiple myeloma, a causal role for this persistent Stat3 activity in oncogenesis has been established, thereby validating Stat3 as a clinically important target for cancer drug discovery. Since currently there are no direct pharmacological inhibitors of Stat3, the goal of this application is to identify potent small molecule Stat3 inhibitors with the potential to be used as cancer therapeutics. We have already made progress in identifying a number of lead compounds selective for inhibition of Stat3 signaling. The central hypothesis of this application is that small-molecule inhibitors of Stat3 signaling will induce growth inhibition and apoptosis in malignant cells, and thereby block tumor growth. The hypothesis will be addressed by the following Specific Aims: (1). To develop small-molecule inhibitors of Stat3 dimerization, DNA-binding and oncogenic signaling. Peptidomimetic approaches will be developed to block dimerization of Stat3 proteins though their SH2 domains. Structure-based and combinatorial methods will be used to convert lead peptides into biologically active agents; (2). To evaluate novel peptidomimetics for potent inhibitory effects against Stat3 and its biological effects in vitro and in whole cells. In vitro DNA binding activity and cell-based reporter assays will be used for screening of compounds. Soft-agar growth, TUNEL assay, and Annexin V-FITC staining will measure biological effects of compounds; (3). To evaluate the antitumor effects of potent compounds identified above in human tumor models in mice. Studies will assess toxicity and degree of efficacy of these compounds against tumors. The proposed studies will refine and further develop lead compounds as potent Stat3 inhibitors with antitumor activities for eventual clinical applications ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA106439-01A1
Application #
6870436
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Forry, Suzanne L
Project Start
2005-02-14
Project End
2005-08-06
Budget Start
2005-02-14
Budget End
2005-08-06
Support Year
1
Fiscal Year
2005
Total Cost
$112,525
Indirect Cost
Name
H. Lee Moffitt Cancer Center & Research Institute
Department
Type
DUNS #
139301956
City
Tampa
State
FL
Country
United States
Zip Code
33612
Zhang, Xiaolei; Yue, Peibin; Page, Brent D G et al. (2012) Orally bioavailable small-molecule inhibitor of transcription factor Stat3 regresses human breast and lung cancer xenografts. Proc Natl Acad Sci U S A 109:9623-8
Mitra, Rajendra N; Doshi, Mona; Zhang, Xiaolei et al. (2012) An activatable multimodal/multifunctional nanoprobe for direct imaging of intracellular drug delivery. Biomaterials 33:1500-8
Yue, P; Zhang, X; Paladino, D et al. (2012) Hyperactive EGF receptor, Jaks and Stat3 signaling promote enhanced colony-forming ability, motility and migration of cisplatin-resistant ovarian cancer cells. Oncogene 31:2309-22
Page, Brent D G; Fletcher, Steven; Yue, Peibin et al. (2011) Identification of a non-phosphorylated, cell permeable, small molecule ligand for the Stat3 SH2 domain. Bioorg Med Chem Lett 21:5605-9
Avadisian, Miriam; Fletcher, Steven; Liu, Baoxu et al. (2011) Artificially induced protein-membrane anchorage with cholesterol-based recognition agents as a new therapeutic concept. Angew Chem Int Ed Engl 50:6248-53
Jaganathan, Soumya; Yue, Peibin; Paladino, David C et al. (2011) A functional nuclear epidermal growth factor receptor, SRC and Stat3 heteromeric complex in pancreatic cancer cells. PLoS One 6:e19605
Shahani, Vijay M; Yue, Peibin; Fletcher, Steven et al. (2011) Design, synthesis, and in vitro characterization of novel hybrid peptidomimetic inhibitors of STAT3 protein. Bioorg Med Chem 19:1823-38
Shahani, Vijay M; Yue, Peibin; Haftchenary, Sina et al. (2011) Identification of Purine-Scaffold Small-Molecule Inhibitors of Stat3 Activation by QSAR Studies. ACS Med Chem Lett 2:79-84
Fletcher, Steven; Page, Brent D G; Zhang, Xialoei et al. (2011) Antagonism of the Stat3-Stat3 protein dimer with salicylic acid based small molecules. ChemMedChem 6:1459-70
Zhao, Wei; Jaganathan, Soumya; Turkson, James (2010) A cell-permeable Stat3 SH2 domain mimetic inhibits Stat3 activation and induces antitumor cell effects in vitro. J Biol Chem 285:35855-65

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