Recently, we have modified the one-bead-one-compound (OBOC) combinatorial library method by adding a known cell adhesion (or cell capturing) ligand to the surface of every bead in the OBOC library. When live cells are incubated with such novel one-bead-two-compound (OB2C) libraries, the cell membranes of the captured cells facing the bead surface are exposed to the library compounds displayed on each bead. With an appropriate reporter system, one should be able to rapidly detect beads that can elicit a specific biochemical or cellular response (agonists). Similarly, if the cells are stimulatd by an exogenous agonist, molecules that suppress specific biochemical or cellular response (antagonists) can also be discovered with this approach. In this R33 proposal, we plan to focus our effort on using the novel OB2C technology to discover pro- apoptotic cell surface acting molecules against both hematologic and solid malignancies.
Specific aims of this proposed project are as follows:
Aim 1 : To design and synthesize OB2C combinatorial libraries for the discovery of synthetic and cell surface acting pro-apoptotic molecules or death ligands.
Aim 2 : To screen OB2C combinatorial libraries for the discovery of synthetic and cell surface acting death ligands against lymphoid cancer, acute myeloid leukemia and solid tumor cells. The lead compounds will be further optimized with focused OB2C combinatorial libraries.
Aim 3 : To resynthesize the lead compounds and evaluate their pro-apoptotic functions by themselves or after conjugation to the cancer cell surface targeting ligands. The mechanisms of action of these pro-apoptotic agents will be determined. Impact: The ultra-high throughput OB2C library method is highly efficient and economical. Once optimized, it can be readily applied by many academic investigators to their research. The death ligands to be developed in this proposed research can be developed into novel effective but less toxic cancer therapeutics. These ligands may also be used as biologically active probes for basic cancer biology and systems biology research, particularly after their mechanisms of action have been elucidated.

Public Health Relevance

In this R33 proposal, we plan to focus our effort on using the novel OB2C technology to discover pro-apoptotic cell surface acting molecules against both hematologic and solid malignancies. These death ligands can be developed into novel effective but less toxic cancer therapeutics. They may also be used as biologically active probes for basic cancer biology and systems biology research, particularly after their mechanisms of action have been elucidated.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
5R33CA160132-03
Application #
8721882
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Li, Jerry
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Davis
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Davis
State
CA
Country
United States
Zip Code
95618
Xiao, Wenwu; Bononi, Fernanda C; Townsend, Jared et al. (2013) Immobilized OBOC combinatorial bead array to facilitate multiplicative screening. Comb Chem High Throughput Screen 16:441-8