STAT proteins (signal transduction and activators of transcription) mediate a variety of extracellular signals. In response to ligand binding to receptor, these proteins become phosphorylated on an invariant tyrosine residue located near the C-terminus. Upon tyrosine phosphorylation, STAT proteins combine to form dimers, in which the SH2 domain of one monomer binds the pTyr of the second and the SH2 domain of the second monomer binds to the pTyr of the first. The dimer then migrates to the nucleus, binds to specific DNA promoter sequences and initiates transcription of designated response elements. In normal cells STATs mediate signaling from growth factor receptors and immune stimuli. However, in several cancer types, STATs are activated constitutively. In this proposal we will focus on Stat3, which has been shown to be constitutively activated in cancers of the breast, colon, and brain. The hypothesis of this proposal is that by blocking the dimerization of Stat3, we can eliminate the signaling mediated by this protein that promotes proliferation and prevents apoptosis and thereby inhibit the growth of tumor cells. To do this we intend to develop peptidomimetics based on phosphotyrosine containing peptides targeted to the Stat3 SH2 domain. We have demonstrated that a phosphopeptide derived from pTyr 705 of Stat3 is capable of inhibiting Stat3 activation in cells. In this grant we will develop inhibitors of Stat3 dimerization by 1. Optimizing amino acid sequences of Stat3 SH2 domain inhibitor peptides. 2. Put constrained tyrosines and other conformational constraints in smallest peptide to lock the conformation for optimal binding interactions. 3. Determine the structure of our peptides bound to the SH2 domain of Stat3 using X-ray crystallography and/or NMR to be used in refinement of our inhibitors. 4. Assay our compounds as inhibitors of dimerization and DNA binding, and test the most promising compounds in cell based assays of growth inhibition, soft agar colony formation, cell viability, and apoptosis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA096652-03
Application #
6757898
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Forry, Suzanne L
Project Start
2002-07-18
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2006-06-30
Support Year
3
Fiscal Year
2004
Total Cost
$335,975
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Neurology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Morlacchi, Pietro; Robertson, Fredika M; Klostergaard, Jim et al. (2014) Targeting SH2 domains in breast cancer. Future Med Chem 6:1909-26
Dhanik, Ankur; McMurray, John S; Kavraki, Lydia E (2013) DINC: a new AutoDock-based protocol for docking large ligands. BMC Struct Biol 13 Suppl 1:S11
Mandal, Pijus K; Ren, Zhiyong; Chen, Xiaomin et al. (2013) Structure-Activity Studies of Phosphopeptidomimetic Prodrugs Targeting the Src Homology 2 (SH2) Domain of Signal Transducer and Activator of Transcription 3 (Stat3). Int J Pept Res Ther 19:3-12
Dhanik, Ankur; McMurray, John S; Kavraki, Lydia E (2012) Binding modes of peptidomimetics designed to inhibit STAT3. PLoS One 7:e51603
McMurray, John S; Mandal, Pijus K; Liao, Warren S et al. (2012) The consequences of selective inhibition of signal transducer and activator of transcription 3 (STAT3) tyrosine705 phosphorylation by phosphopeptide mimetic prodrugs targeting the Src homology 2 (SH2) domain. JAKSTAT 1:263-347
Auzenne, Edmond J; Klostergaard, Jim; Mandal, Pijus K et al. (2012) A phosphopeptide mimetic prodrug targeting the SH2 domain of Stat3 inhibits tumor growth and angiogenesis. J Exp Ther Oncol 10:155-62
Dhanik, Ankur; McMurray, John S; Kavraki, Lydia (2011) On modeling peptidomimetics in complex with the SH2 domain of Stat3. Conf Proc IEEE Eng Med Biol Soc 2011:3229-32
Mandal, Pijus K; Gao, Fengqin; Lu, Zhen et al. (2011) Potent and selective phosphopeptide mimetic prodrugs targeted to the Src homology 2 (SH2) domain of signal transducer and activator of transcription 3. J Med Chem 54:3549-63
Mandal, Pijus K; Freiter, Eric M; Bagsby, Allison L et al. (2011) Efficient synthesis of apricoxib, CS-706, a selective cyclooxygenase-2 inhibitor, and evaluation of inhibition of prostaglandin E2 production in inflammatory breast cancer cells. Bioorg Med Chem Lett 21:6071-3
Baameur, Faiza; Morgan, Daniel H; Yao, Hui et al. (2010) Role for the regulator of G-protein signaling homology domain of G protein-coupled receptor kinases 5 and 6 in beta 2-adrenergic receptor and rhodopsin phosphorylation. Mol Pharmacol 77:405-15

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