The goal of this application is to rationally design, synthesize, and evaluate certain nucleoside analogs in an effort to discover new agents for the treatment of solid tumors as well as hematological malignancies. The key investigators of this project have been involved in this endeavor for many years and have recently been responsible for the discovery of a new drug (clofarabine) that was approved by the FDA for the treatment of childhood acute lymphocytic leukemia in December of 2004 and is currently being evaluated in adult clinical trials for activity in solid tumors and hematological malignancies. Recently, we have discovered a lead compound that is modified at the 2'- and 4'-positions that has demonstrated excellent activity against solid tumor xenografts in mice. Only a few analogs in this series have been made with anticancer activity as the disease target, and it is the goal of this proposal to thoroughly evaluate the potential of this type of modification. The application consists of two specific aims.
In aim 1 we will design and synthesize novel nucleoside analogs with modifications at the 4'-carbon. The target compounds are rationally designed based on our extensive knowledge of nucleoside metabolism, the analogs that are currently used in the treatment of cancer, available protein structural data, computational modeling with dCyd kinase and those compounds that have been made in the past by us and others. All new compounds will be tested for cytotoxicity against a panel of human solid tumor cell lines. Cytotoxic compounds will be evaluated for toxicity to normal cells, and those compounds with significant selectivity will be synthesized in sufficient quantities for in vivo studies to determine antitumor efficacy against numerous human solid tumor xenografts.
In specific aim 2 we will evaluate the metabolism and mechanism of action of new agents with promising activity so that we can learn how these compounds differ from existing agents. The results of the biological evaluations will be used in the iterative rational design of new compounds. This grant application is a highly integrated effort involving expertise in the design and synthesis of nucleoside analogs, the biochemical evaluation of the metabolism and mechanism of action of nucleoside analogs, and the evaluation of new agents in human tumor xenografts. The grant application is focused on the discovery of new anticancer agents based on an established anticancer drug class, and is expected to lead to a clinical candidate as well as to increase our understanding of the mechanisms of action of this important class. In this proposal we will design, synthesize, and evaluate new nucleoside analogs as anticancer agents based upon a new lead compound with activity in animal model systems. The key investigators of this project have been involved in anticancer drug discovery for many years and have recently been responsible for the discovery of a new drug (clofarabine), which was recently approved by the FDA for the treatment of childhood acute lymphocytic leukemia and is currently being evaluated in adult clinical trials for activity in solid tumors and hematological malignancies.
|Waud, William R; Parker, William B; Gilbert, Karen S et al. (2012) Isolation and characterization of a murine P388 leukemia line resistant to thiarabine. Nucleosides Nucleotides Nucleic Acids 31:14-27|
|Waud, William R; Gilbert, Karen S; Secrist 3rd, John A (2012) Preclinical antitumor activity of thiarabine in human leukemia and lymphoma xenograft models. Nucleosides Nucleotides Nucleic Acids 31:647-60|
|Waud, William R; Gilbert, Karen S; Secrist 3rd, John A (2012) Preclinical combination therapy of thiarabine plus various clinical anticancer agents. Nucleosides Nucleotides Nucleic Acids 31:630-46|
|Waud, William R; Gilbert, Karen S; Secrist 3rd, John A (2011) Lack of in vivo cross-resistance with 4'-thio-ara-C against drug-resistant murine P388 and L1210 leukemias. Cancer Chemother Pharmacol 68:399-403|
|Parker, William B (2009) Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer. Chem Rev 109:2880-93|