This project involves the application of the """"""""one-bead one-compound"""""""" encoded small molecule combinational library method and chemical microarray technique to study functional proteomics. Five enormous libraries of small molecule ligands (a total of over 1 million compounds) will be generated and screened against whole cell extracts derived from a B lymphoma cell line (Ramos). Billions of possible molecular interactions will be examined concurrently. Beads containing compounds that bind to cellular proteins or protein complexes will be isolated and the compound chemical structure determined by our novel decoding method. Selected small molecule ligands will be resynthesized on Sepharose beads and used as affinity matrix to capture the binding proteins or protein-complexes. The identity of the bound proteins will then be determined by protein separation and mass spectroscopy. Based on the chemical structure of these ligands, a small molecule microarray (approximately 1000 compounds) will be developed to probe the functional state of the whole cell extract. Our hypothesis is that with the above experimental scheme, we can systematically select a finite number of small molecule ligands and use them as capturing agents to probe the functional state of a B lymphoma cell. We further hypothesize that some of the ligands that bind to unique protein targets in lymphoma cell can be used as lead compounds for the development of anti-lymphoma agents. Once validated in a large number of lymphoid malignant cell lines, peripheral blood lymphocytes, and a limited number of primary malignant lymphoid tissues, this microarray technology can be applied to biopsy specimens obtained from a large number of patients with lymphoid malignancies. This technique, if successful, can readily be applied to other cancer types as well.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
5R33CA099136-02
Application #
6747255
Study Section
Special Emphasis Panel (ZCA1-SRRB-C (O1))
Program Officer
Forry, Suzanne L
Project Start
2003-06-01
Project End
2006-05-31
Budget Start
2004-07-19
Budget End
2005-05-31
Support Year
2
Fiscal Year
2004
Total Cost
$358,504
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Xiao, Wenwu; Wang, Yan; Lau, Edmond Y et al. (2010) The use of one-bead one-compound combinatorial library technology to discover high-affinity ?v?3 integrin and cancer targeting arginine-glycine-aspartic acid ligands with a built-in handle. Mol Cancer Ther 9:2714-23
Xiao, Wenwu; Yao, Nianhuan; Peng, Li et al. (2009) Near-infrared optical imaging in glioblastoma xenograft with ligand-targeting alpha 3 integrin. Eur J Nucl Med Mol Imaging 36:94-103
Baek, Hyoung Gee; Liu, Ruiwu; Lam, Kit S (2009) Development of hydrogel TentaGel shell-core beads for ultrahigh throughput solution-phase screening of encoded OBOC combinatorial small molecule libraries. J Comb Chem 11:91-102
Miyamoto, Suzanne; Liu, Ruiwu; Hung, Susan et al. (2008) Screening of a one bead-one compound combinatorial library for beta-actin identifies molecules active toward Ramos B-lymphoma cells. Anal Biochem 374:112-20
Park, See-Hyoung; Wang, Xiaobing; Liu, Ruiwu et al. (2008) High throughput screening of a small molecule one-bead-one-compound combinatorial library to identify attenuators of p21 as chemotherapy sensitizers. Cancer Biol Ther 7:2015-22
Yao, Nianhuan; Wu, Chun-Yi; Xiao, Wenwu et al. (2008) Discovery of high-affinity peptide ligands for vancomycin. Biopolymers 90:421-32
Peng, Li; Liu, Ruiwu; Andrei, Mirela et al. (2008) In vivo optical imaging of human lymphoma xenograft using a library-derived peptidomimetic against alpha4beta1 integrin. Mol Cancer Ther 7:432-7
Yao, Nianhuan; Song, Aiming; Wang, Xiaobing et al. (2007) Synthesis of flavonoid analogues as scaffolds for natural product-based combinatorial libraries. J Comb Chem 9:668-76
Peng, Li; Liu, Ruiwu; Marik, Jan et al. (2006) Combinatorial chemistry identifies high-affinity peptidomimetics against alpha4beta1 integrin for in vivo tumor imaging. Nat Chem Biol 2:381-9
Liu, Ruiwu; Peng, Li; Han, Huijun et al. (2006) Structure-activity relationship studies of a series of peptidomimetic ligands for alpha(4) beta(1) integrin on Jurkat T-leukemia cells. Biopolymers 84:595-604

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