The overall goal of this NCDDG is to develop our lymphoid cancer targeting peptidomimetic leads into useful therapeutic and imaging agents. Through combinatorial chemistry, we have identified a series of peptidomimetic compounds that bind to activated alpha4beta1 of lymphoid malignancies. These compounds contain an organic moiety, D-amino acids, and unnatural amino acids, and therefore they are expected to be resistant to proteolysis. They bind to both T- and B-lymphoma cell lines as well as fresh leukemia cells derived from patients with acute lymphocytic leukemia, but they do not bind to normal human peripheral blood. Furthermore, they bind strongly to dog lymphoma cells. These peptidomimetic leads have great potential to be developed into therapeutic and imaging agents for both human and canine lymphoid malignancies. This NCDDG application has three programs and two cores. Program 1 is responsible for further optimization and characterization of these peptidomimetic leads. Computational chemistry and combinatorial chemistry will be used for lead optimization. Program 2 involves the use of a series of CHO cells, that have been stably transfected with wild type or mutant alpha4 and/or beta1 integrin genes, to evaluate the molecular interactions between alpha4beta1 integrin and the targeting agents developed in Program 1. This study will enable us to map the binding site, and to develop high affinity ligand analogues that can overcome the mutation of the critical residues on the integrin. Program 3 involves in vivo evaluation of the targeting agents, developed in Program 1 and synthesized by Core B. DOTA-labeled targeting agents will be loaded with 64Cu for PET imaging and 90Y for therapeutics studies in nude mice with human lymphoma xenograft, and in spontaneous canine lymphoma in companion dog. The synthetic chemistry core (Core B), with input from corresponding programs, will be responsible for the design and synthesis of compound-bead libaries, targeting agents, and any other chemical conjugates required by all three programs. Program 1, 2, and 3 as well as Core B are highly interactive and synergistic. Our goal is to fully optimize and evaluate the targeting potential of our radio-targeting agents for lymphoid malignancies by the end of year 5, at which time one targeting agent will be selected for clinical development.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19CA113298-04
Application #
7430432
Study Section
Special Emphasis Panel (ZCA1-SRRB-U (J1))
Program Officer
Song, Min-Kyung H
Project Start
2005-08-19
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
4
Fiscal Year
2008
Total Cost
$1,031,038
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
Zwingenberger, Allison L; Kent, Michael S; Liu, Ruiwu et al. (2012) In-vivo biodistribution and safety of 99mTc-LLP2A-HYNIC in canine non-Hodgkin lymphoma. PLoS One 7:e34404
Yao, Nianhuan; Chen, Chao-Yu; Wu, Chun-Yi et al. (2011) Novel flavonoids with antiproliferative activities against breast cancer cells. J Med Chem 54:4339-49
Kumaresan, Pappanaicken R; Wang, Yan; Saunders, Mary et al. (2011) Rapid discovery of death ligands with one-bead-two-compound combinatorial library methods. ACS Comb Sci 13:259-64
Luo, Juntao; Xiao, Kai; Li, Yuanpei et al. (2010) Well-defined, size-tunable, multifunctional micelles for efficient paclitaxel delivery for cancer treatment. Bioconjug Chem 21:1216-24
Yamaji, Satoshi; Saegusa, Jun; Ieguchi, Katsuaki et al. (2010) A novel fibroblast growth factor-1 (FGF1) mutant that acts as an FGF antagonist. PLoS One 5:e10273
Carpenter, Richard D; Kurth, Mark J (2010) A rapid and efficient route to benzazole heterocycles. Nat Protoc 5:1731-6
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
Yao, Nianhuan; Fung, Gabriel; Malekan, Hamed et al. (2010) Facile synthesis of glycosylated Fmoc amino acid building blocks assisted by microwave irradiation. Carbohydr Res 345:2277-81
Townsend, Jared B; Shaheen, Farzana; Liu, Ruiwu et al. (2010) Jeffamine derivatized TentaGel beads and poly(dimethylsiloxane) microbead cassettes for ultrahigh-throughput in situ releasable solution-phase cell-based screening of one-bead-one-compound combinatorial small molecule libraries. J Comb Chem 12:700-12

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