The main focus of our laboratory is to develop new techniques in combinatorial chemistry and chemical microarray and to apply them to basic research and drug discovery. The """"""""one-bead one-compound"""""""" (OBOC) combinatorial library method was invented by our laboratory over a decade ago (Lam et al. 1991). Since then, it has been successfully applied to the identification of ligands for a large number of biological targets (Lam et al. 1997). The OBOC method is highly efficient, especially when used with well-established on-bead binding or functional assays. Literally millions of compounds can be screened concurrently within a few days. This method has primarily been used on peptide libraries in the past, but we believe that similar success can be accomplished with small molecule bead-libraries. While the OBOC technique is the ultimate high-throughput method, a major limitation with combinatorial small molecule bead libraries is the difficulty in elucidating the chemical structure of a small molecule compound on one single bead. A rapid, sensitive, and reliable encoding/decoding methodology is necessary for full exploitation of the OBOC combinatorial method. We propose to use topologically segregated bi-functional beads with testing molecules on the outer layer of the bead and the coding molecules placed in the interior, in conjunction with a novel encoding scheme for small molecule bead-libraries which can be readily decoded by mass spectroscopy (MALDI-FTMS). We hypothesize that from such libraries we would be able to efficiently identify small molecule ligands for various intracellular protein targets, and that these small molecule ligands would be able to exert biological effects on intact cells. We plan to apply the method to the discovery of p60c-src protein tyrosine kinase (PTK) inhibitors.
Specific aims of this proposal are as follows: 1. To optimize a novel encoding system, for the OBOC combinatorial small molecule libraries, that can be easily and reliably decoded by mass spectroscopy and applicable to many different coupling chemistries in library synthesis. 2. To design, synthesize, and screen ten different encoded OBOC combinatorial small molecule libraries with a total of over 2 million compounds, and to identify and optimize ligands that bind to p60c-src PTK. 3. To evaluate the enzyme inhibitory activity and cellular effects of the identified p60c-src PTK ligands.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA098116-02
Application #
6752090
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Fu, Yali
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
2
Fiscal Year
2004
Total Cost
$319,405
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
Guo, W; Liu, R; Bhardwaj, G et al. (2014) Targeting Btk/Etk of prostate cancer cells by a novel dual inhibitor. Cell Death Dis 5:e1409
Guo, Wenchang; Liu, Ruiwu; Bhardwaj, Gaurav et al. (2013) CTA095, a novel Etk and Src dual inhibitor, induces apoptosis in prostate cancer cells and overcomes resistance to Src inhibitors. PLoS One 8:e70910
Guo, Wenchang; Liu, Ruiwu; Ono, Yoko et al. (2012) Molecular characteristics of CTA056, a novel interleukin-2-inducible T-cell kinase inhibitor that selectively targets malignant T cells and modulates oncomirs. Mol Pharmacol 82:938-47
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; 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
Marik, Jan; Lam, Kit S (2005) Peptide and small-molecule microarrays. Methods Mol Biol 310:217-26
Wang, Xiaobing; Peng, Li; Liu, Ruiwu et al. (2005) Partial alloc-deprotection approach for ladder synthesis of ""one-bead one-compound"" combinatorial libraries. J Comb Chem 7:197-209
Song, Aimin; Zhang, Jinhua; Lebrilla, Carlito B et al. (2004) Solid-phase synthesis and spectral properties of 2-alkylthio-6H-pyrano[2,3-f]benzimidazole-6-ones: a combinatorial approach for 2-alkylthioimidazocoumarins. J Comb Chem 6:604-10

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